JP7508501B2 - Nucleotide and nucleoside compositions and related uses - Google Patents

Description

This application claims priority to U.S. Provisional Application No. 61/876,473, filed September 11, 2013; U.S. Provisional Application No. 61/923,317, filed January 3, 2014; and U.S. Provisional Application No. 61/986,577, filed April 30, 2014, the disclosures of which are incorporated herein by reference.

This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to sulfur-containing nucleosides optionally conjugated to a phosphorus oxide or a salt thereof. In certain embodiments, the disclosure relates to conjugate compounds comprising an amino acid ester, lipid or sphingolipid or derivative linked to a nucleotide or nucleoside by a phosphorus oxide, or a salt thereof. In certain embodiments, the disclosure contemplates pharmaceutical compositions comprising these compounds for use in treating infectious diseases, viral infections, and cancer.

Nucleoside and nucleotide phosphates and phosphonates are clinically useful as antiviral agents. Two examples are tenofovir disoproxil fumarate for the treatment of human immunodeficiency virus and adefovir dipivoxil for the treatment of hepatitis B virus infection. Administration of three or more antiretroviral agents in combination, e.g., highly active antiretroviral therapy (HAART), has significantly reduced morbidity and mortality associated with HIV infection. However, there is an increasing need for new antiviral agents to address the significant challenges of resistance and entry into viral sanctuaries (commonly referred to as privileged compartments). Penetration into privileged compartments may be partially responsible for the current inability of chemotherapy to completely eliminate HIV infection from patients and the emergence of resistance.

Antivirals that are non-phosphorylated nucleotides and nucleotide derivatives need to be phosphorylated to actively inhibit viral replication. Nucleoside analogues enter cells via two types of broad specificity transporters, the concentrative nucleoside transporter (CNT) and the equilibrative nucleoside transporter (ENT). Once inside, they exploit the host's nucleoside salvage pathway for sequential phosphorylation by deoxynucleoside kinase (dNK), deoxynucleoside monophosphate kinase (dNMPK) and nucleoside diphosphate kinase (NDPK). However, the intracellular activation of these compounds is often compromised by the high substrate specificity of the host's endogenous kinases. In vitro and in vivo studies have demonstrated that the first and/or second phosphorylation catalyzed by dNK and dNMPK often represents the rate-limiting step in nucleoside analogue activation. Thus, there is a need to identify improved antiviral nucleoside analogues that have structural features that allow them to be fully activated by cellular kinases.

McGuigan et al., J Med Chem, 2005, 48(10), 3504-3515, reported that the phenylmethoxyalaninyl phosphoramidate of abacavir as a prodrug led to enhanced antiviral efficacy. Painter et al., Antimicrob Agents Chemother, 2007, 51(10), 3505-3509, reported enhanced oral availability of tenofovir with a hexadecyloxypropyl prodrug ester, designated CMX157.

Sphingolipids play a role in cell-cell and cell-substratum interactions and help regulate growth and differentiation by various mechanisms, such as inhibition of growth factor receptor kinases and effects on multiple cell signaling systems. US Patent No. 6,610,835 discloses sphingosine analogs. It also discloses methods for treating infections and cancer. Pruett et al., J. Lipid Res. 2008, 49(8), 1621-1639, report on sphingosine and derivatives. Bushnev et al., ARKIVOC, 2010, (viii):263-277, report on asymmetric synthetic methods for preparing sphingolipid derivatives. Dougherty et al., Org. Lett. 2006, 8(4), 649-652, report on the synthesis of 1-deoxysphingosine derivatives. Wiseman et al., Org. Lett. 2005, 7(15), 3155-3157, report 1-deoxy-5-hydroxysphingolipids in anticancer and stereoselective synthesis of 2-amino-3,5-diols.

The references cited herein are not admissions of prior art.

U.S. Pat. No. 6,610,835

McGuigan et al., J Med Chem, 2005, 48(10), 3504-3515 Painter et al., Antimicrob Agents Chemother, 2007, 51(10), 3505-3509 Pruett et al., J. Lipid Res. 2008, 49(8), 1621-1639 Bushnev et al., ARKIVOC, 2010, (viii): 263-277 Dougherty et al., Org. Lett. 2006, 8(4), 649-652 Wiseman et al., Org. Lett. 2005, 7(15), 3155-3157

(Summary of the Invention)
This disclosure relates to nucleotide and nucleoside therapeutic compositions and their associated uses.Includes sulfur-containing nucleosides or salts thereof optionally conjugated to phosphorus oxides, prodrugs or conjugate compounds or salts thereof that include amino acid esters, lipids or sphingolipids or derivatives linked to nucleotides or nucleosides by phosphorus oxides.

FIG. 1 illustrates certain embodiments of the disclosure. FIG. 1 illustrates exemplary thio-containing bases for certain embodiments provided herein. FIG. 1 illustrates the elucidation of McGuigan prodrugs in vivo. The metabolic elucidation of these prodrugs begins with an esterase-catalyzed cleavage of the carboxylic acid ester, followed by several chemical rearrangement steps to yield the amino acid phosphoramidate. The final cleavage is carried out by one of several endogenous phosphoramidases, one of which has been identified as histidine triad nucleotide-binding protein 1 (hINT1). FIG. 1 illustrates embodiments of mono- and diphosphate structure types. FIG. 1 illustrates a scheme for the synthesis of a conjugate. FIG. 1 is the X-ray crystal structure of EIDD-02023.

This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses related thereto. In certain embodiments, the disclosure relates to sulfur-containing nucleosides or salts thereof, optionally conjugated to a phosphorus oxide. In certain embodiments, the disclosure relates to conjugated compounds comprising an amino acid ester, lipid or sphingolipid or derivative linked to a nucleotide or nucleoside by a phosphorus oxide, or salts thereof. In certain embodiments, the disclosure contemplates pharmaceutical compositions comprising these compounds for use in treating infectious diseases, viral infections, and cancer.

In certain embodiments, the disclosure relates to phosphorus oxide prodrugs of 2'-fluoronucleosides containing sulfur-containing bases for the treatment of positive-sense and negative-sense RNA viral infections via targeting virally encoded RNA-dependent RA polymerase (RdRp). The disclosure also provides the general use of lipids and sphingolipids to deliver nucleoside analogs for the treatment of infectious diseases and cancer.

In certain embodiments, the disclosure relates to a conjugate compound or salt thereof comprising a sphingolipid or derivative linked to a nucleotide or nucleoside by a phosphorus oxide, where the nucleotide or nucleoside contains a sulfur-containing base. In certain embodiments, the phosphorus oxide is a phosphate, phosphonate, polyphosphate, or polyphosphonate, where the phosphate in the phosphate, phosphonate, or polyphosphate or polyphosphonate is optionally a phosphorothioate or phosphoroamidate. In certain embodiments, the lipid or sphingolipid is covalently attached to the phosphorus oxide via an amino group or a hydroxyl group.

A nucleotide or nucleoside contains a heterocycle containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where the substituted heterocycle may be substituted with one or more of the same or different alkyl, halogen, or cycloalkyl.

In certain embodiments, the heterocycle containing two or more nitrogen heteroatoms is substituted with at least one thione, thiol, or thioether, or is selected from pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, or 4-amino-5-fluoropyrimidine-2-thione.

In certain embodiments, the sphingolipid is a saturated or unsaturated 2-aminoalkyl or 2-aminooctadecane, which may be substituted with one or more substituents. In certain embodiments, the sphingolipid derivative is a saturated or unsaturated 2-aminooctadecane-3-ol, which may be substituted with one or more substituents. In certain embodiments, the sphingolipid derivative is a saturated or unsaturated 2-aminooctadecane-3,5-diol, which may be substituted with one or more substituents.

In certain embodiments, the disclosure contemplates a pharmaceutical composition comprising any of the compounds disclosed herein and a pharma- ceutical acceptable excipient. In certain embodiments, the pharmaceutical composition is in the form of a pill, capsule, tablet, or saline buffer that includes the polysaccharide. In certain embodiments, the composition can contain a second active agent, such as a pain relieving agent, an anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, an antiviral agent, an antibiotic agent, or an anti-cancer agent.

In certain embodiments, the disclosure relates to a method of treating or preventing an infection comprising administering to a subject in need thereof an effective amount of a compound disclosed herein. Typically, the subject has been diagnosed with or is at risk for having an infection from a virus, bacteria, fungus, protozoa, or parasite.

In certain embodiments, the disclosure relates to a method of treating a viral infection comprising administering an effective amount of a pharmaceutical composition disclosed herein to a subject in need thereof. In certain embodiments, the subject is a mammal, e.g., a human. In certain embodiments, the subject has been diagnosed with a chronic viral infection. In certain embodiments, the administration is under conditions such that the viral infection is no longer detectable. In certain embodiments, the subject has been diagnosed with an RNA virus, a DNA virus, or a retrovirus. In certain embodiments, the subject has been diagnosed with a virus that is a double-stranded DNA virus, a sense single-stranded DNA virus, a double-stranded RNA virus, a sense single-stranded RNA virus, an antisense single-stranded RNA virus, a sense single-stranded RNA retrovirus, or a double-stranded DNA retrovirus.

In certain embodiments, the subject is infected with influenza A virus, including subtypes H1N1, H3N2, H7N9, or H5N1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, human coronavirus, SARS coronavirus, MERS coronavirus, human adenovirus types (HAdV-1 to 55), human papillomavirus (HPV) types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, Coxsackie A virus, norovirus, rubella virus, lymphocytic choriomeningitis virus (LCCHV), lymphocytic choriomeningitis virus (LCH ... MV), dengue virus, chikungunya, eastern equine encephalitis virus (EEEV), western equine encephalitis virus (WEEV), Venezuelan equine encephalitis virus (VEEV), yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, rinderpest virus, California encephalitis virus, hantavirus, rabies virus, Ebola virus, Marburg virus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes lymphotropic virus, roseolovirus or Kaposi's sarcoma-associated herpes virus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, or human immunodeficiency virus (HIV).

In certain embodiments, the subject is infected with influenza A virus, including subtypes H1N1, H3N2, H7N9, H5N1 (low pass) and H5N1 (high pass), influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, SARS coronavirus, MERS-CoV, human adenovirus types (HAdV-1 to 55), human papilloma virus, HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, Coxsackie A virus, norovirus, rubella virus, lymphocytic choriomeningitis virus (LCMV), yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, parahidrosis virus, Influenza virus 1 and 3, Rinderpest virus, Chikungunya, Eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), Western equine encephalitis virus (WEEV), California encephalitis virus, Japanese encephalitis virus, Rift Valley fever virus (RVFV), Hantavirus, Dengue virus serotypes 1, 2, 3 and 4, West Nile virus, Tacaribe virus, Junin, Rabies virus, Ebola virus, Marble Have been diagnosed with HIV, adenovirus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes lymphotropic virus, roseolovirus, or Kaposi's sarcoma-associated herpes virus, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, or human immunodeficiency virus (HIV).

In certain embodiments, the subject has been diagnosed with gastroenteritis, acute respiratory disease, severe acute respiratory syndrome, post-viral fatigue syndrome, viral hemorrhagic fever, acquired immune deficiency syndrome, or hepatitis.

In certain embodiments, the pharmaceutical compositions disclosed herein comprise abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, type III interferon, type II interferon, type I interferon, laminidine, ramiclovir ... It is administered in combination with a second antiviral agent, such as vudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, sofosvovir, stavudine, telaprevir, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir or zidovudine, and combinations thereof.

In certain embodiments, the disclosure relates to a method of treating cancer comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition disclosed herein. In certain embodiments, the cancer is selected from bladder cancer, lung cancer, breast cancer, melanoma, colon and rectal cancer, non-Hodgkin's lymphoma, endometrial cancer, pancreatic cancer, kidney cancer, prostate cancer, leukemia, thyroid cancer, and brain cancer.

In certain embodiments, the composition is selected from the group consisting of temozolomide, bevacizumab, procarbazine, lolimustine, vincristine, gefitinib, erlotinib, docetaxel, cisplatin, 5-fluorouracil, gemcitabine, tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin, vinblastine, vindesine, vinorelbine, taxol, taxotere, etoposide, teniposide, amsac and/or a combination of a second anticancer agent, such as cyclosporine, topotecan, camptothecin, bortezomib, anagrelide, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, fulvestrant, bicalutamide, flutamide, nilutamide, cyproterone, goserelin, leuprorelin, buserelin, megestrol, anastrozole, letrozole, borazole, exemestane, finasteride, marimastat, trastuzumab, cetuximab, dasatinib, imatinib, combretastatin, thalidomide and/or lenalidomide, or a combination thereof.

In certain embodiments, the disclosure relates to the use of the compounds disclosed herein in the production or manufacture of a medicament for the treatment or prevention of an infectious disease, a viral infection, or cancer.

In certain embodiments, the disclosure relates to derivatives of any of the compounds or formulas disclosed herein.

Additional advantages of the disclosure will be described in part in the description which follows. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not limitations of the disclosure as claimed.

It is to be understood that this disclosure is not limited to the particular embodiments described. The scope of the present disclosure will be limited only by the appended claims, and it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are described here.

All publications and patents cited in this specification are incorporated by reference herein as if each individual publication or patent was specifically and individually indicated to be incorporated by reference, and are incorporated by reference herein to disclose and describe the methods and/or materials related to the methods and/or materials to which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by reason of prior disclosure. Further, the dates of publication provided may differ from the actual publication dates which may need to be independently confirmed.

As will be apparent to one of ordinary skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and features that may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method may be carried out in the order of events recited or in any other order that is logically possible.

The embodiments of the present disclosure employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art. Such techniques are fully explained in the literature.

As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the content clearly indicates otherwise. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings unless a contrary intention is apparent.

Prior to describing the various embodiments, the following definitions are provided and should be used unless otherwise indicated.

As used herein, the term "phosphorus oxide" refers to any of a variety of chemical moieties that contain a phosphorus-oxygen (P-0 or P=O) bond. When used herein as a linking group, the conjugated molecule can be attached to the oxygen or directly to the phosphorus atom. The term is intended to include, but is not limited to, phosphates, where the phosphorus is typically attached to four oxygens, and phosphonates, where the phosphorus is typically attached to one carbon and three oxygens. "Polyphosphate" generally refers to phosphates that are linked together by at least one phosphorus-oxygen-phosphorus (P-O-P) bond. "Polyphosphonate" refers to polyphosphates that contain at least one phosphorus-carbon (C-P-O-P) bond. In addition to containing phosphorus-oxygen bonds, phosphorus oxides can contain phosphorus-thiol (P-S or P=S) bonds and/or phosphorus-amine (P-N) bonds, referred to as phosphorothioates or phosphoramidates, respectively. In phosphorus oxides, the oxygen atom can form double or single bonds or combinations to the phosphorus, the oxygen can be further bonded to other atoms such as carbon, or can exist as anions in equilibrium with cations, e.g., metals or quaternary amines.

As used herein, "alkyl" means an acyclic, cyclic, linear or branched unsaturated or saturated hydrocarbon, such as those containing 1 to 22 carbon atoms, specifically including methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. The term includes both substituted and unsubstituted alkyl groups. The alkyl group may be, for example, one or more moieties selected from hydroxyl, amino, halo, deutero, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate or phosphonate, or as known to those skilled in the art, for example, as described in T. W. Greene and P. G. M., herein incorporated by reference. Wuts, "Protective Groups in Organic Synthesis", 3rd Edition, John Wiley & Sons, 1999, may be substituted with any other viable functional group, either unprotected or protected as appropriate, that does not interfere with the pharmacological activity of the compound.

The term "lower alkyl," as used herein and unless otherwise specified, refers to a C1 to C4 saturated straight-chain, branched, or, where appropriate, cyclic (e.g., cyclopropyl) alkyl group, including both substituted and unsubstituted forms. Unless otherwise specifically stated in this application, when alkyl is a suitable component, lower alkyl is preferred.

The term "halo" or "halogen" as used herein includes chloro, bromo, iodo and fluoro.

Non-aromatic monocyclic or polycyclic alkyls are referred to herein as "carbocyclic" or "carbocyclyl" groups containing from 3 to 30 carbon atoms. Representative saturated carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, while unsaturated carbocyclic rings include cyclopentenyl and cyclohexenyl.

A "heterocarbocycle" or "heterocarbocyclyl" group is a carbon ring containing one to four heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, in which the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.

"Aryl" means an aromatic carbocyclic monocyclic or polycyclic ring containing from 6 to 32 carbon atoms, such as phenyl or naphthyl. Polycyclic ring systems can, but need not, contain one or more non-aromatic rings as long as one of the rings is aromatic.

As used herein, "heteroaryl" refers to an aromatic heterocarbocycle having from one to four heteroatoms selected from nitrogen, oxygen, and sulfur and containing at least one carbon atom, including both monocyclic and polycyclic ring systems. Polycyclic ring systems can, but need not, contain one or more non-aromatic rings as long as one of the rings is aromatic. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. Use of the term "heteroaryl" is intended to include N-alkylated derivatives such as 1-methylimidazol-5-yl substituents.

As used herein, "heterocycle" or "heterocyclyl" refers to monocyclic and polycyclic ring systems having one to four heteroatoms selected from nitrogen, oxygen, and sulfur and containing at least one carbon atom. The monocyclic and polycyclic ring systems may be aromatic, non-aromatic, or mixtures of aromatic and non-aromatic rings. Heterocycles include heterocarbocycles, heteroaryls, and the like.

"Alkylthio" refers to an alkyl group as defined above attached through a sulfur bridge. An example of an alkylthio group is methylthio (ie, --S--CH ₃ ).

"Alkoxy" refers to an alkyl group as defined above attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, and t-butoxy.

"Alkylamino" refers to an alkyl group as defined above attached through an amino bridge. An example of an alkylamino is methylamino (ie, --NH--CH ₃ ).

"Alkanoyl" refers to an alkyl as defined above attached through a carbonyl bridge (i.e., -(C=O)alkyl).

"Alkylsulfonyl" refers to an alkyl as defined above attached through a sulfonyl bridge (i.e., -S(=O) _2alkyl ), such as mesyl, and "arylsulfonyl" refers to an aryl attached through a sulfonyl bridge (i.e., -S(=O) _2aryl ).

"Alkylsulfinyl" refers to an alkyl as defined above attached through a sulfinyl bridge (i.e., -S(=O)alkyl).

The term "substituted" refers to a molecule in which at least one hydrogen atom has been replaced with a substituent. When substituted, one or more of the group is a "substituent." The molecule may be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Exemplary substituents in this context may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, -NRaC(=O)ORb, _-NRaSO2Rb , -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, -SRa, -SORa, -S(=O) _2Ra , -OS(=O) _2Ra and -S(=O) _2ORa . Ra and Rb in this context may be the same or different and may independently be hydrogen, halogen, hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl.

The term "optionally substituted" as used herein means that it may be substituted, so that it is possible for the specified atom to be unsubstituted.

As used herein, "salt" refers to derivatives of the disclosed compounds, where the parent compound is modified to make its acid or base salt. Examples of salts include, but are not limited to, mineral or organic acid salts of basic residues, such as amines, alkylamines, or dialkylamines; alkali or organic salts of acidic residues, such as carboxylic acids; and the like. In typical embodiments, the salts are conventional non-toxic pharma-ceutically acceptable salts of the parent compound formed, including quaternary ammonium salts of non-toxic inorganic or organic acids. Preferred salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid.

"Subject" refers to any animal, preferably a human patient, livestock, rodent, monkey or household pet.

The term "prodrug" refers to an agent that is converted into a biologically active form in vivo. Prodrugs are often useful because, in some situations, they may be more convenient to administer than the parent compound. They may, for example, be bioavailable by oral administration, whereas the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may also be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.

As used herein, the term "derivative" refers to a structurally similar compound that retains sufficient functional attributes of the identified analog. A derivative may be structurally similar because it lacks one or more atoms, is substituted with one or more substituents, is a salt, is in a different hydration/oxidation state, for example, substitutes a single or double bond, substitutes a hydroxy group for a ketone, or has one or more atoms exchanged within the molecule, for example, but not limited to, replacing an oxygen atom with a sulfur or nitrogen atom, or replacing an amino group with a hydroxyl group, or vice versa. Substituting a carbon with a nitrogen in an aromatic ring is a contemplated derivative. The derivative may be a prodrug. The derivatives can be prepared by any of a variety of synthetic methods or suitable adaptations found in the chemical literature or in synthetic or organic chemistry textbooks, such as those provided in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith, or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze, which are incorporated herein by reference.

As used herein, the terms "prevent" and "preventing" include the total or partial inhibition of the recurrence, spread, or onset of the referenced condition or disease. The disclosure is not intended to be limited to complete prevention. In some embodiments, onset is delayed or the severity of the disease is reduced.

As used herein, the terms "treat" and "treating" are not limited to cases where a subject (e.g., a patient) is cured and the disease is eradicated. Rather, embodiments of the present disclosure also contemplate treatments that merely reduce symptoms and/or slow disease progression.

As used herein, the term "in combination with" when used to describe administration with an additional treatment means that the agent can be administered before, together with, or after the additional treatment, or a combination thereof.

Nucleoside analogs as antiviral agents Nucleoside analogs exploit the host's nucleoside salvage pathway for sequential phosphorylation by deoxynucleoside kinase (dNK), deoxynucleoside monophosphate kinase (dNMPK) and nucleoside diphosphate kinase (NDPK). However, the intracellular activation of these compounds is often compromised by the high substrate specificity of the host's endogenous kinases. In vitro and in vivo studies have demonstrated that the first and/or second phosphorylation catalyzed by dNK and dNMPK often represents the rate-limiting step in nucleoside analog activation. These significant blockages in the phosphorylation cascade of a given nucleoside analog result in the lack of any observable activity in cellular assays. To circumvent these blockages, several kinase bypass strategies have been developed. For example, McGuigan phosphoramidates are chemical conjugates used for kinase bypass. See Serpi et al., J Med Chem, 2012, 55(10):4629-4639. Metabolism of these prodrugs begins with an esterase-catalyzed cleavage of the carboxylic acid ester, followed by several chemical rearrangement steps to yield the amino acid phosphoramidate. The final cleavage is carried out by one of several endogenous phosphoramidases, one of which has been identified as histidine triad nucleotide-binding protein 1 (hINT1).

An alternative prodrug strategy to circumvent these blockades is to utilize sphingoid bases to mask nucleotide analog phosphates. Sphingoid bases have the potential to deliver nucleotide analog phosphates to critical tissues such as the brain. The design concept driving the use of sphingoid bases to form nucleoside-lipid conjugates is based on the observations that sphingoid base analogs (a) are well absorbed after oral administration, (b) are resistant to oxidative catabolism in enterocytes, and (c) achieve high concentrations in the brain. Based on data on the intestinal uptake of traditional phospholipid drug conjugates in mice and our data on sphingoid base oral absorption in rats, our sphingoid base conjugates should be well absorbed and resist first-pass metabolism. After absorption, sphingoid bases, including sphingosine-1-phosphate, are transported into the blood via both lipoproteins and free plasma proteins such as albumin. Active epithelial cell uptake of sphingoid base phosphates has been demonstrated to occur via the ABC transporter, CFTR, although passive protein transport and endocytic uptake are also possible, and extracellularly delivered drug conjugates are believed to be similarly processed by target cells in the central nervous system (CNS) and gut-associated lymphoid tissue (GALT). The rat sphingolipid PK study described above resulted in 24-hour tissue concentrations that exceeded plasma Cmax concentrations by 10 to 300+ fold, with lung and brain levels being particularly high, and without evidence of toxicity. This approach has significant potential for delivery of high drug concentrations of conjugates to critical tissues.

Compounds In certain embodiments, the disclosure relates to nucleosides having a sulfur-containing base conjugated to a phosphorus moiety, or a pharma- ceutically acceptable salt thereof.

In a particular embodiment, the present invention provides a compound of the formula:

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Ｕは、ＯまたはＳであり；
Ｘは、Ｏ、ＣＨ_２またはＣＤ_２であり；
Ｒ^１は、モノホスフェート、ジホスフェート、トリホスフェートおよびポリホスフェート、またはポリホスホネートを含めて、ホスホネート、ホスホノホスフェート、ホスホノジホスフェートまたはホスフェートであり；
ここで、ホスホネートまたはポリホスフェートにおけるホスフェートは、場合によって、ホスホロボレート、ホスホロチオエートまたはホスホロアミデートであり；
ここで、ホスホネート、またはポリホスフェート、ホスホロボレート、ホスホロチオレートもしくはホスホロアミデートにおけるホスフェートは、１つ以上の同一であるまたは異なるＲ^８で置換されてもよく；
ここで、ホスホネート、またはポリホスフェート、ホスホロボレート、ホスホロチオレートもしくはホスホロアミデートにおけるホスフェートは、複素環式環を含有するリンを場合によって形成し；
ここで、ホスホネート、ホスホノホスフェート、ホスホノジホスフェート、ホスフェート、ポリホスフェート、ポリホスホネート、ホスホロチオレートまたはホスホロアミデートは、Ｒ^３またはＲ^４炭素を有する複素環式環を含有するリンを場合によって形成し；
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^６、Ｒ^７およびＲ^８は、独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＣＨ_３、ＣＤ_３、ＣＦ_３、ＣＦ_２Ｈ、ＣＦＨ_２、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、ＮＯ_２、Ｃ（Ｏ）Ｏ（Ｃ_１－２２アルキル）、Ｃ（Ｏ）Ｏ（Ｃ_１－２２アルキル）、Ｃ（Ｏ）Ｏ（Ｃ_１－２２アルキニル）、Ｃ（Ｏ）Ｏ（Ｃ_１－２２アルケニル）、Ｏ（Ｃ_１－２２アシル）、Ｏ（Ｃ_１－２２アルキル）、Ｏ（Ｃ_１－２２アルケニル）、Ｓ（Ｃ_１－２２アシル）、Ｓ（Ｃ_１－２２アルキル）、Ｓ（Ｃ_１－２２アルキニル）、Ｓ（Ｃ_１－２２アルケニル）、ＳＯ（Ｃ_１－２２アシル）、ＳＯ（Ｃ_１－２２アルキル）、ＳＯ（Ｃ_１－２２アルキニル）、ＳＯ（Ｃ_１－２２アルケニル）、ＳＯ_２（Ｃ_１－２２アシル）、ＳＯ_２（Ｃ_１－２２アルキル）、ＳＯ_２（Ｃ_１－２２アルキニル）、ＳＯ_２（Ｃ_１－２２アルケニル）、Ｏ_３Ｓ（Ｃ_１－２２アシル）、Ｏ_３Ｓ（Ｃ_１－２２アルキル）、Ｏ_３Ｓ（Ｃ_１－２２アルケニル）、ＮＨ_２、ＮＨ（Ｃ_１－２２アルキル）、ＮＨ（Ｃ_１－２２アルケニル）、ＮＨ（Ｃ_１－２２アルキニル）、ＮＨ（Ｃ_１－２２アシル）、Ｎ（Ｃ_１－２２アルキル）_２、Ｎ（Ｃ_１－２２アシル）_２、スルファモイル、Ｎ－メチルカルバモイル、Ｎ－エチルカルバモイル、Ｎ，Ｎ－ジメチルカルバモイル、Ｎ，Ｎ－ジエチルカルバモイル、Ｎ－メチル－Ｎ－エチルカルバモイル、メチルスルフィニル、エチルスルフィニル、メシル、エチルスルホニル、メトキシカルボニル、エトキシカルボニル、Ｎ－メチルスルファモイル、Ｎ－エチルスルファモイル、Ｎ，Ｎ－ジメチルスルファモイル、Ｎ，Ｎ－ジエチルスルファモイル、Ｎ－メチル－Ｎ－エチルスルファモイル、またはカルボシクリルであり；
ここで、アルキル、アルキニル、アルケニルおよびビニルは、Ｎ_３、ＣＮ、１つから３つのハロゲン（Ｃｌ、Ｂｒ、Ｆ、Ｉ）、重水素、ＮＯ_２、Ｃ（Ｏ）Ｏ（Ｃ_１－２２アルキル）、Ｃ（Ｏ）Ｏ（Ｃ_１－２２アルキル）、Ｃ（Ｏ）Ｏ（Ｃ_１－２２アルキニル）、Ｃ（Ｏ）Ｏ（Ｃ_１－２２アルケニル）、Ｏ（Ｃ_１－２２アシル）、Ｏ（Ｃ_１－２２アルキル）、Ｏ（Ｃ_１－２２アルケニル）、Ｓ（Ｃ_１－２２アシル）、Ｓ（Ｃ_１－２２アルキル）、Ｓ（Ｃ_１－２２アルキニル）、Ｓ（Ｃ_１－２２アルケニル）、ＳＯ（Ｃ_１－２２アシル）、ＳＯ（Ｃ_１－２２アルキル）、ＳＯ（Ｃ_１－２２アルキニル）、ＳＯ（Ｃ_１－２２アルケニル）、ＳＯ_２（Ｃ_１－２２アシル）、ＳＯ_２（Ｃ_１－２２アルキル）、ＳＯ_２（Ｃ_１－２２アルキニル）、ＳＯ_２（Ｃ_１－２２アルケニル）、Ｏ_３Ｓ（Ｃ_１－２２アシル）、Ｏ_３Ｓ（Ｃ_１－２２アルキル）、Ｏ_３Ｓ（Ｃ_１－２２アルケニル）、ＮＨ_２、ＮＨ（Ｃ_１－２２アルキル）、ＮＨ（Ｃ_１－２２アルケニル）、ＮＨ（Ｃ_１－２２アルキニル）、ＮＨ（Ｃ_１－２２アシル）、Ｎ（Ｃ_１－２２アルキル）_２、Ｎ（Ｃ_１－２２アシル）_２、スルファモイル、Ｎ－メチルカルバモイル、Ｎ－エチルカルバモイル、Ｎ，Ｎ－ジメチルカルバモイル、Ｎ，Ｎ－ジエチルカルバモイル、Ｎ－メチル－Ｎ－エチルカルバモイル、メチルスルフィニル、エチルスルフィニル、メシル、エチルスルホニル、メトキシカルボニル、エトキシカルボニル、Ｎ－メチルスルファモイル、Ｎ－エチルスルファモイル、Ｎ，Ｎ－ジメチルスルファモイル、Ｎ，Ｎ－ジエチルスルファモイル、Ｎ－メチル－Ｎ－エチルスルファモイル、またはカルボシクリルによって置換されてもよく；
Ｒ^５は、ＨまたはＤであり；
Ｑは、少なくとも１つのチオン、チオールまたはチオエーテルで置換されている２個以上の窒素ヘテロ原子を含むヘテロシクリルであり、ここでＱは、１つ以上の同一であるまたは異なるアルキル、ハロゲン、シクロアルキルで置換されてもよい。

or a pharma- ceutical acceptable salt thereof, wherein
U is O or S;
X is O, _CH2 or _CD2 ;
^R1 is a phosphonate, phosphonophosphate, phosphonodiphosphate or phosphate, including monophosphate, diphosphate, triphosphate and polyphosphate, or polyphosphonate;
wherein the phosphate in the phosphonate or polyphosphate is optionally a phosphoroborate, phosphorothioate, or phosphoramidate;
wherein the phosphate in the phosphonate, or polyphosphate, phosphoroborate, phosphorothiolate or phosphoramidate may be substituted with one or more identical or different R ⁸ ;
wherein the phosphate in the phosphonate, or polyphosphate, phosphoroborate, phosphorothiolate, or phosphoramidate optionally forms a phosphorus containing heterocyclic ring;
wherein the phosphonate, phosphonophosphate, phosphonodiphosphate, phosphate, polyphosphate, polyphosphonate, phosphorothiolate, or phosphoroamidate optionally forms a phosphorus containing heterocyclic ring with the ^R3 or ^R4 carbon;
R ² , R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁸ are independently H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, CH ₃ , CD ₃ , CF ₃ , CF ₂ H, CFH ₂ , OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, NO ₂ , C(O)O(C _1-22 alkyl), C(O)O(C _1-22 alkyl), C(O)O(C _1-22 alkynyl), C(O)O(C _1-22 alkenyl), O(C _1-22 acyl), O(C _1-22 alkyl), O(C _1-22 alkenyl), S(C _1-22 acyl), S(C _1-22 alkyl), S(C _1-22 alkynyl), S(C _1-22 alkenyl), SO(C _1-22 acyl), SO(C _1-22 alkyl), SO(C _1-22 alkynyl), SO(C _1-22 alkenyl), SO ₂ (C _1-22 acyl), SO ₂ (C _1-22 alkyl), SO ₂ (C _1-22 alkynyl), SO ₂ (C _1-22 alkenyl), O ₃ S(C _1-22 acyl), O ₃ S(C _1-22 alkyl), O ₃ S(C _1-22 alkenyl), NH ₂ , NH(C _1-22 alkyl), NH(C _1-22 alkenyl), NH(C _1-22 alkynyl), NH(C _1-22 acyl), N(C _1-22 alkyl) ₂ , N(C _1-22 acyl) ₂ , sulfamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, or carbocyclyl;
Here, alkyl, alkynyl, alkenyl and vinyl are N ₃ , CN, one to three halogens (Cl, Br, F, I), deuterium, NO ₂ , C(O)O(C _1-22 alkyl), C(O)O(C _1-22 alkyl), C(O)O(C _1-22 alkynyl), C(O)O(C _1-22 alkenyl), O(C _1-22 acyl), O(C _1-22 alkyl), O(C _1-22 alkenyl), S(C _1-22 acyl), S(C _1-22 alkyl), S(C _1-22 alkynyl), S(C _1-22 alkenyl), SO(C _1-22 acyl), SO(C _1-22 alkyl), SO(C _{1-22 alkynyl), SO(C 1-22 alkenyl} ), SO ₂ (C _1-22 acyl), SO ₂ (C _1-22 alkyl), SO ₂ (C _1-22 alkynyl), SO ₂ (C _1-22 alkenyl), O ₃ S (C _1-22 acyl), O ₃ S (C _1-22 alkyl), O ₃ S (C _1-22 alkenyl), NH ₂ , NH (C _1-22 alkyl), NH (C _1-22 alkenyl), NH (C _1-22 alkynyl), NH (C _1-22 acyl), N (C _1-22 alkyl) ₂ , N (C _1-22 acyl) ₂ , sulfamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, or carbocyclyl;
^R5 is H or D;
Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl.

In certain embodiments, Q heterocyclyl is selected from pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

In a preferred embodiment, U is O and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine. In another preferred embodiment, U is S and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine.

In a preferred embodiment, the nucleoside conjugated to the phosphorus moiety or a pharma- ceutical acceptable salt thereof has the following structure:

またはこの医薬として許容される塩を有し、式中、
Ｕは、ＯまたはＳであり；
Ｘは、ＣＨ_２またはＣＤ_２であり；
Ｒ^１は、ＯＨ、モノホスフェート、ジホスフェートまたはトリホスフェートであり；
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^６およびＲ^７は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^９で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^９は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
Ｒ^５は、ＨまたはＤであり；
Ｑは、以下の塩基：

or a pharma- ceutical acceptable salt thereof, wherein:
U is O or S;
X is _CH2 or _CD2 ;
^R1 is OH, monophosphate, diphosphate or triphosphate;
R ² , R ³ , R ⁴ , R ⁶ and R ⁷ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ⁹ ;
Each ^R9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
^R5 is H or D;
Q is the following base:

（式中、Ζは、アルキル、アルキエニル、アシル、脂質またはゲラニルである。）
の１つである。

(wherein Z is alkyl, alkyenyl, acyl, lipid or geranyl).
This is one of them.

In certain embodiments, ^R2 is selected from the group _consisting of H, D, _CH3 , CD3, _CF3 , _CF2H , _CFH2 , _CH2OH , _CH2Cl , CCH, OH, SH, _NH2 , _N3 , CHO, CN, Cl, Br, F, or I. In one embodiment, ^R2 is H.

In another specific embodiment, ^R3 is selected from the group _consisting of H, D, _CH3 , CD3, _CF3 , _CF2H , _CFH2 , _CH2OH , _CH2Cl , CCH, OH, SH, _NH2 , _N3 , CHO, CN, Cl, Br, F or I.

In yet another specific embodiment, ^R4 is selected from the group _consisting of H, D, _CH3 , CD3, _CF3 , _CF2H , _CFH2 , _CH2OH , _CH2Cl , CCH, OH, SH, _NH2 , _N3 , CHO, CN, Cl, Br, F or I.

In further specific embodiments, ^R6 is selected from the group _consisting of H, D, _CH3 , CD3, _CF3 , _CF2H , _CFH2 , _CH2OH , _CH2Cl , CCH, OH, SH, _NH2 , _N3 , CHO, CN, Cl, Br, F or I.

In yet another specific embodiment, ^R7 is selected from the group consisting of H, D, _CH3 , CD3, _CF3 , _CF2H , _CFH2 , _CH2OH , _CH2Cl , CCH, OH _, SH, NH2, _N3 , CHO, CN, Cl, _Br , F or I.

Lipids, as used herein, are C _6-22 alkyl, alkoxy, polyethylene glycol or aryl substituted with an alkyl group.

In certain embodiments, the lipids are fatty alcohols, fatty amines, or fatty thiols derived from essential and non-essential fatty acids.

In certain embodiments, the lipids are unsaturated, polyunsaturated, omega-unsaturated or omega-polyunsaturated fatty alcohols, fatty amines or fatty thiols derived from essential and non-essential fatty acids.

In certain embodiments, lipids are fatty alcohols, fatty amines, or fatty thiols derived from essential and non-essential fatty acids in which one or more of their carbon units have been replaced with oxygen, nitrogen, or sulfur.

In certain embodiments, the lipids are unsaturated, polyunsaturated, omega-unsaturated or omega-polyunsaturated fatty alcohols, fatty amines or fatty thiols derived from essential and non-essential fatty acids, in which one or more of their carbon units are replaced by oxygen, nitrogen or sulfur.

In certain embodiments, the lipids are fatty alcohols, fatty amines, or fatty thiols derived from essential and non-essential fatty acids, which may be substituted.

In certain embodiments, the lipids are unsaturated, polyunsaturated, omega-unsaturated or omega-polyunsaturated fatty alcohols, fatty amines or fatty thiols derived from essential and non-essential fatty acids, which may be substituted.

In certain embodiments, the lipids are fatty alcohols, fatty amines, or fatty thiols derived from essential and non-essential fatty acids, one or more of whose carbon units are substituted with optionally substituted oxygen, nitrogen, or sulfur.

In certain embodiments, the lipids are unsaturated, polyunsaturated, omega-unsaturated or omega-polyunsaturated fatty alcohols, fatty amines or fatty thiols derived from essential and non-essential fatty acids, one or more of whose carbon units are replaced with oxygen, nitrogen or sulfur, which may also be substituted.

In one particular embodiment, the lipid is hexadecyloxypropyl.

In one particular embodiment, the lipid is 2-aminohexadecyloxypropyl.

In certain embodiments, the lipid is 2-aminoarachidyl.

In certain embodiments, the lipid is 2-benzyloxyhexadecyloxypropyl.

In certain embodiments, the lipid is lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, or lignoceryl.

In certain embodiments, the lipid has the formula:

を有するスフィンゴ脂質であり、式中、
スフィンゴ脂質のＲ^８は、水素、アルキル、Ｃ（＝Ｏ）Ｒ^１２、Ｃ（＝Ｏ）ＯＲ^１２またはＣ（＝Ｏ）ＮＨＲ^１２であり；
スフィンゴ脂質のＲ^９は、水素、フルオロ、ＯＲ^１２、ＯＣ（＝Ｏ）Ｒ^１２、ＯＣ（＝Ｏ）ＯＲ^１２、またはＯＣ（＝Ｏ）ＮＨＲ^１２であり；
スフィンゴ脂質のＲ^１０は、１つ以上のハロゲンもしくはヒドロキシで置換されてもよい６個超および２２個未満の炭素の飽和もしくは不飽和アルキル鎖、または以下の式：

A sphingolipid having the formula:
R ⁸ of the sphingolipid is hydrogen, alkyl, C(═O)R ¹² , C(═O)OR ¹² or C(═O)NHR ¹² ;
R ⁹ of the sphingolipid is hydrogen, fluoro, OR ¹² , OC(═O)R ¹² , OC(═O)OR ¹² , or OC(═O)NHR ¹² ;
R ¹⁰ of the sphingolipid is a saturated or unsaturated alkyl chain of more than 6 and less than 22 carbons, which may be substituted with one or more halogens or hydroxy, or a group represented by the following formula:

（ｎは、８から１４もしくは８以下から１４以下であり、ｏは、９から１５もしくは９以下から１５以下であり、ｍおよびｎの合計は、８から１４もしくは８以下から１４以下であり、ｍおよびｏの合計は、９から１５もしくは９以下から１５以下である。）；もしくは

wherein n is from 8 to 14 or from 8 to 14 inclusive, o is from 9 to 15 or from 9 to 15 inclusive, the sum of m and n is from 8 to 14 or from 8 to 14 inclusive, and the sum of m and o is from 9 to 15 or from 9 to 15 inclusive; or

（ｎは、４から１０もしくは４以下から１０以下であり、ｏは、５から１１もしくは５以下から１１以下であり、ｍおよびｎの合計は、４から１０もしくは４以下から１０以下であり、ｍおよびｏの合計は、５から１１もしくは５以下から１１以下である。）；もしくは

wherein n is 4 to 10 or 4 or less to 10 or less, o is 5 to 11 or 5 or less to 11 or less, the sum of m and n is 4 to 10 or 4 or less to 10 or less, and the sum of m and o is 5 to 11 or 5 or less to 11 or less; or

（ｎは６から１２であるもしくはｎは６以下から１２以下であり、ｍおよびｎの合計は６から１２であるもしくはｎは６以下から１２以下である。）
の構造であり；
スフィンゴ脂質のＲ^１１は、ＯＲ^１２、ＯＣ（＝Ｏ）Ｒ^１２、ＯＣ（＝Ｏ）ＯＲ^１２またはＯＣ（＝Ｏ）ＮＨＲ^１２であり；
スフィンゴ脂質のＲ^１２は、水素、分岐もしくは直鎖のＣ_１－１２アルキル、Ｃ_{１３－２２}アルキル、シクロアルキル、またはベンジルもしくはフェニルから選択されるアリールであり、ここでアリールは、１つ以上の同一であるまたは異なるＲ^１３で置換されてもよく；
スフィンゴ脂質のＲ^１３は、ハロゲン、ニトロ、シアノ、ヒドロキシ、トリフルオロメトキシ、トリフルオロメチル、アミノ、ホルミル、カルボキシ、カルバモイル、メルカプト、スルファモイル、メチル、エチル、メトキシ、エトキシ、アセチル、アセトキシ、メチルアミノ、エチルアミノ、ジメチルアミノ、ジエチルアミノ、Ｎ－メチル－Ｎ－エチルアミノ、アセチルアミノ、Ｎ－メチルカルバモイル、Ｎ－エチルカルバモイル、Ｎ，Ｎ－ジメチルカルバモイル、Ｎ，Ｎ－ジエチルカルバモイル、Ｎ－メチル－Ｎ－エチルカルバモイル、メチルチオ、エチルチオ、メチルスルフィニル、エチルスルフィニル、メシル、エチルスルホニル、メトキシカルボニル、エトキシカルボニル、Ｎ－メチルスルファモイル、Ｎ－エチルスルファモイル、Ｎ，Ｎ－ジメチルスルファモイル、Ｎ，Ｎ－ジエチルスルファモイル、Ｎ－メチル－Ｎ－エチルスルファモイル、カルボシクリル、アリール、またはヘテロシクリルである。

(n is 6 to 12, or n is 6 or less to 12, and the sum of m and n is 6 to 12, or n is 6 or less to 12.)
The structure is
R ¹¹ of the sphingolipid is OR ¹² , OC(═O)R ¹² , OC(═O)OR ¹² or OC(═O)NHR ¹² ;
R ¹² of the sphingolipid is hydrogen, branched or straight chain C _1-12 alkyl, C _13-22 alkyl, cycloalkyl, or aryl selected from benzyl or phenyl, where the aryl is optionally substituted with one or more identical or different R ¹³ ;
R ¹³ of the sphingolipid is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, R ¹² of the sphingolipid is H, alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenyl, mono-substituted phenyl, di-substituted phenyl, tri-substituted phenyl, or saturated or unsaturated C12-C19 long chain alkyl.

In certain embodiments, the sphingolipid has the formula:

を有し、式中、
スフィンゴ脂質のＲ^８は、水素、ヒドロキシ、フルオロ、ＯＲ^１２、ＯＣ（＝Ｏ）Ｒ^１２、ＯＣ（＝Ｏ）ＯＲ^１２またはＯＣ（＝Ｏ）ＮＨＲ^１２であり；
スフィンゴ脂質のＲ^９は、水素、ヒドロキシ、フルオロ、ＯＲ^１２、ＯＣ（＝Ｏ）Ｒ^１２、ＯＣ（＝Ｏ）ＯＲ^１２またはＯＣ（＝Ｏ）ＮＨＲ^１２であり；
スフィンゴ脂質のＲ^１０は、１つ以上のハロゲンで置換されてもよい６個超および２２個未満の炭素の飽和もしくは不飽和アルキル鎖、または以下の式：

wherein
R ⁸ of the sphingolipid is hydrogen, hydroxy, fluoro, OR ¹² , OC(═O)R ¹² , OC(═O)OR ¹² or OC(═O)NHR ¹² ;
R ⁹ of the sphingolipid is hydrogen, hydroxy, fluoro, OR ¹² , OC(═O)R ¹² , OC(═O)OR ¹² or OC(═O)NHR ¹² ;
R ¹⁰ of the sphingolipid is a saturated or unsaturated alkyl chain of more than 6 and less than 22 carbons, optionally substituted with one or more halogens, or a group represented by the following formula:

（ｎは、８から１４もしくは８以下から１４以下、ｍおよびｎの合計は、８から１４もしくは８以下から１４以下である。）
の構造であり；
スフィンゴ脂質のＲ^１２は、水素、分岐もしくは直鎖Ｃ_１－１２アルキル、Ｃ_{１３－２２}アルキル、シクロアルキル、またはベンジルもしくはフェニルから選択されるアリールであり、ここでアリールは、１つ以上の同一であるまたは異なるＲ^１３で置換されてもよく；
スフィンゴ脂質のＲ^１３は、ハロゲン、ニトロ、シアノ、ヒドロキシ、トリフルオロメトキシ、トリフルオロメチル、アミノ、ホルミル、カルボキシ、カルバモイル、メルカプト、スルファモイル、メチル、エチル、メトキシ、エトキシ、アセチル、アセトキシ、メチルアミノ、エチルアミノ、ジメチルアミノ、ジエチルアミノ、Ｎ－メチル－Ｎ－エチルアミノ、アセチルアミノ、Ｎ－メチルカルバモイル、Ｎ－エチルカルバモイル、Ｎ，Ｎ－ジメチルカルバモイル、Ｎ，Ｎ－ジエチルカルバモイル、Ｎ－メチル－Ｎ－エチルカルバモイル、メチルチオ、エチルチオ、メチルスルフィニル、エチルスルフィニル、メシル、エチルスルホニル、メトキシカルボニル、エトキシカルボニル、Ｎ－メチルスルファモイル、Ｎ－エチルスルファモイル、Ｎ，Ｎ－ジメチルスルファモイル、Ｎ，Ｎ－ジエチルスルファモイル、Ｎ－メチル－Ｎ－エチルスルファモイル、カルボシクリル、アリール、またはヘテロシクリルである。

(n is 8 to 14 or 8 or less to 14 or less, and the sum of m and n is 8 to 14 or 8 or less to 14 or less.)
The structure is
R ¹² of the sphingolipid is hydrogen, branched or straight chain C _1-12 alkyl, C _13-22 alkyl, cycloalkyl, or aryl selected from benzyl or phenyl, where the aryl is optionally substituted with one or more identical or different R ¹³ ;
R ¹³ of the sphingolipid is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, R ¹² of the sphingolipid is H, alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenyl, mono-substituted phenyl, di-substituted phenyl, tri-substituted phenyl, or saturated or unsaturated C ₁₂ -C ₁₉ long chain alkyl.

Suitable sphingolipids include, but are not limited to, sphingosine, ceramide or sphingomyelin, or 2-aminoalkyl, which may be substituted with one or more substituents.

Other suitable sphingolipids include, but are not limited to, 2-aminooctadecane-3,5-diol; (2S,3S,5S)-2-aminooctadecane-3,5-diol; (2S,3R,5S)-2-aminooctadecane-3,5-diol; 2-(methylamino)octadecane-3,5-diol; (2S,3R,5S)-2-(methylamino)octadecane-3,5-diol; 2-(dimethylamino)octadecane-3,5-diol; (2R,3S,5S)-2-(dimethylamino)octadecane-3,5-diol; 1-(pyrrolidin-2-yl)hexadecane-1,3-diol; (1S,3S)-1-((S )-pyrrolidin-2-yl)hexadecane-1,3-diol; 2-amino-11,11-difluorooctadecane-3,5-diol; (2S,3S,5S)-2-amino-11,11-difluorooctadecane-3,5-diol; 11,11-difluoro-2-(methylamino)octadecane-3,5-diol; (2S,3S,5S)-11,11-difluoro-2-(methylamino)octadecane-3,5-diol; N-((2S,3S,5S)-3,5-dihydroxyoctadecane-2-yl)acetamide; N-((2S,3S,5S)-3,5-dihydroxyoctadecane-2-yl)palmitamide; 1- (1-aminocyclopropyl)hexadecane-1,3-diol; (1S,3R)-1-(1-aminocyclopropyl)hexadecane-1,3-diol; (1S,3S)-1-(1-aminocyclopropyl)hexadecane-1,3-diol; 2-amino-2-methyloctadecane-3,5-diol; (3S,5S)-2-amino-2-methyloctadecane-3,5-diol; (3S,5R)-2-amino-2-methyloctadecane-3,5-diol; (3S,5S)-2-methyl-2-(methylamino)octadecane-3,5-diol; 2-amino-5-hydroxy-2-methyloctadecane-3-one; (Z)- These include 2-amino-5-hydroxy-2-methyloctadecane-3-one oxime; (2S,3R,5R)-2-amino-6,6-difluorooctadecane-3,5-diol; (2S,3S,5R)-2-amino-6,6-difluorooctadecane-3,5-diol; (2S,3S,5S)-2-amino-6,6-difluorooctadecane-3,5-diol; (2S,3R,5S)-2-amino-6,6-difluorooctadecane-3,5-diol; and (2S,3S,5S)-2-amino-18,18,18-trifluorooctadecane-3,5-diol; which may be substituted with one or more substituents.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこれらの医薬として許容される塩に関し、式中、
Ｕは、ＯまたはＳであり；
Ｙは、ＯまたはＳであり；
Ｙ’は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｑは、少なくとも１つのチオン、チオールまたはチオエーテルで置換されている２個以上の窒素ヘテロ原子を含むヘテロシクリルであり、ここでＱは、１つ以上の同一であるまたは異なるアルキル、ハロゲンまたはシクロアルキルで置換されてもよく；
Ｒ^３、Ｒ^４、Ｒ^６、Ｒ^７およびＲ^８は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^９で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^９は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
Ｒ^５は、ＨまたはＤである。

or a pharma- ceutical acceptable salt thereof, wherein
U is O or S;
Y is O or S;
Y' is OH or BH ₃ ⁻ M ⁺ ;
Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl;
R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁸ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ⁹ ;
Each ^R9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
^R5 is H or D.

In certain embodiments, Q is a heterocycle selected from the group consisting of pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

In a preferred embodiment, U is O and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine. In another preferred embodiment, U is S and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine.

In one embodiment, ^R3 is selected from the group _consisting of H, D, _CH3 , CD3, _CF3 , _CF2H , _CFH2 , _CH2OH , _CH2Cl , CCH, OH, SH, _NH2 , _N3 , CHO, CN, Cl, Br, F or I.

In another embodiment, ^R4 is selected from the group consisting of H, _CH3 , CD3 _{, CF3, CF2H, CFH2, CH2OH, CH2Cl , CCH , OH ,} SH, _NH2 , _N3 , CHO, CN, Cl, Br, F or I.

In yet another embodiment, ^R6 is selected from the group _{consisting of H, CH3, CD3, CF3, CF2H, CFH2, CH2OH, CH2Cl , CCH , OH , SH} , _NH2 , _N3 , CHO, CN, Cl, Br, F or I.

In yet another embodiment, ^R7 is selected from the group _{consisting of H, CH3, CD3, CF3, CF2H, CFH2, CH2OH, CH2Cl , CCH , OH , SH} , _NH2 , _N3 , CHO, CN, Cl, Br, F or I.

In still further embodiments, ^R8 is selected from the group _{consisting of H, CH3, CD3, CF3, CF2H, CFH2, CH2OH, CH2Cl , CCH , OH , SH} , _NH2 , _N3 , CHO, CN, Cl, Br, F or I. In one embodiment, ^R8 is H.

In certain embodiments, the disclosure provides a compound of the formula:

の１つの化合物またはこれらの医薬として許容される塩に関し、式中、
Ａは、ＯまたはＳであり；
Ａ’は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ^５は、ＨまたはＤであり；
Ｕは、ＯまたはＳであり；
各Ｘは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
Ｒ^１は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^８、ＳＲ^８、ＮＨＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
ここで、式ＩｃおよびＩｄにおいて、ＸがＳであるもしくはＲ^１がＳＲ^８であるのいずれか、またはＸがＳであるおよびＲ^１がＳＲ^８である両方であり；
ここで、式Ｉｅにおいて、少なくとも１つのＸはＳであり；
Ｙは、ＣＨ、ＮまたはＣＲ^２であり；
Ｚは、ＣＨ、ＮまたはＣＲ^２であり；
Ｒ^３、Ｒ^４、Ｒ^６、Ｒ^７およびＲ^１０は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^９で置換されてもよいＣ_１－２２アルキルから選択され；
Ｒ^８は、メチル、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上同一であるまたは異なるＲ^９で置換されてもよいＣ_１－２２アルキルであり；
各Ｒ^９は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
Ｒ^２は、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、１つ以上の同一であるまたは異なるＲ^９で置換されてもよいＣ_１－２２アルキルである。

or a pharma- ceutically acceptable salt thereof, wherein
A is O or S;
A' is OH or BH ₃ ⁻ M ⁺ ;
^R5 is H or D;
U is O or S;
Each X is independently O, S, NH, ^NR8 , NHOH, ^NR8OH , ^{NHOR8 , or NR8OR8 ;
R1} is OH, SH, _NH2 , ^OR8 , ^SR8 , ^NHR8 , NHOH, ^NR8OH , ^{NHOR8 or NR8OR8 ;}
wherein in formulae Ic and Id, either X is S or R ¹ is SR ⁸ , or both X is S and R ¹ is SR ⁸ ;
wherein in formula Ie, at least one X is S;
Y is CH, N or ^CR2 ;
Z is CH, N or ^CR2 ;
R ³ , R ⁴ , R ⁶ , R ⁷ and R ¹⁰ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more of the same or different R ⁹ ;
R ⁸ is methyl, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more identical or different R ⁹ ;
Each ^R9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
R ² is methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, halogenated alkyl, hydroxyl alkyl, acyl, C _1-22 alkyl optionally substituted with one or more of the same or different R ⁹ .

In one embodiment, ^R3 is selected from the group _consisting of H, D, _CH3 , CD3, _CF3 , _CF2H , _CFH2 , _CH2OH , _CH2Cl , CCH, OH, SH, _NH2 , _N3 , CHO, CN, Cl, Br, F or I.

In another embodiment, ^R4 is selected from the group _consisting of H, D, _CH3 , CD3, _CF3 , _CF2H , _CFH2 , _CH2OH , _CH2Cl , CCH, OH, SH, _NH2 , _N3 , CHO, CN, Cl, Br, F or I.

In yet another embodiment, ^R6 is selected from the group _consisting of H, D, _CH3 , CD3, _CF3 , _CF2H , _CFH2 , _CH2OH , _CH2Cl , CCH, OH, SH, _NH2 , _N3 , CHO, CN, Cl, Br, F or I.

In yet another embodiment, ^R7 is selected from the group _consisting of H, D, _CH3 , CD3, _CF3 , _CF2H , _CFH2 , _CH2OH , _CH2Cl , CCH, OH, SH, _NH2 , _N3 , CHO, CN, Cl, Br, F or I.

In yet a further embodiment, R ¹⁰ is selected from the group consisting of H, D, CH ₃ , CD ₃ , CF ₃ , CF ₂ H, CFH ₂ , CH ₂ OH, CH ₂ Cl, CCH, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F or I. In one embodiment, R ⁸ is H.

In certain embodiments, U is S and Y and Z are CH.

In other embodiments, U is O and Y and Z are CH.

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is methyl. In yet another embodiment, ^R7 is fluoro. In yet a further embodiment, ^R10 is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is trifluoromethyl. In yet another embodiment, ^R7 is fluoro. In yet a further embodiment, ^R10 is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is C≡CHmethyl. In yet another embodiment, ^R7 is fluoro. In yet a further embodiment, ^R10 is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is _CH2F . In yet another embodiment, ^R7 is fluoro. In yet a further embodiment, ^R10 is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, R ³ is H. In another embodiment, R ⁴ is H. In a further embodiment, R ⁵ is H. In yet another embodiment, R ⁶ is H. In yet another embodiment, R ⁷ is fluoro. In yet a further embodiment, R ¹⁰ is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is H. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is methyl. In yet another embodiment, ^R7 is fluoro. In yet a further embodiment, ^R10 is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, R ³ is H. In another embodiment, R ⁴ is H. In a further embodiment, R ⁵ is H. In yet another embodiment, R ⁶ is trifluoromethyl. In yet another embodiment, R ⁷ is fluoro. In yet a further embodiment, R ¹⁰ is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is methyl. In yet another embodiment, ^R7 is hydroxyl. In yet a further embodiment, ^R10 is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is trifluoromethyl. In yet another embodiment, ^R7 is hydroxyl. In yet a further embodiment, ^R10 is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is C≡CH. In yet another embodiment, ^R7 is hydroxyl. In yet a further embodiment, ^R10 is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is _CH2F . In yet another embodiment, ^R7 is hydroxyl. In yet a further embodiment, ^R10 is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is methyl. In yet another embodiment, ^R7 is H. In yet a further embodiment, ^R10 is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is trifluoromethyl. In yet another embodiment, ^R7 is H. In yet a further embodiment, ^R10 is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is _N3 . In yet another embodiment, ^R6 is H. In yet another embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is C≡CH. In yet another embodiment, ^R6 is H. In yet another embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is _CH2F . In yet another embodiment, ^R6 is H. In yet another embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is _N3 . In yet another embodiment, ^R6 is H. In yet another embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is C≡CH. In yet another embodiment, ^R6 is H. In yet another embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is _CH2F . In yet another embodiment, ^R6 is H. In yet another embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is fluoro. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is H. In yet another embodiment, ^R6 is H. In yet another embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is fluoro. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is H. In yet another embodiment, ^R6 is methyl. In yet another embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is fluoro. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is H. In yet another embodiment, ^R6 is C≡CH. In yet another embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is fluoro. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is H. In yet another embodiment, ^R6 is _CH2F . In yet another embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is fluoro. In yet another embodiment, ^R6 is methyl. In yet another embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is fluoro. In yet another embodiment, ^R6 is C≡CH. In yet another embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is fluoro. In yet another embodiment, ^R6 is _CH2F . In yet another embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is fluoro. In yet another embodiment, ^R6 is methyl. In yet another embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is fluoro. In yet another embodiment, ^R6 is C≡CH. In yet another embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R3 is H. In another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In another embodiment, ^R10 is fluoro. In yet another embodiment, ^R6 is _CH2F . In yet another embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｕは、ＯまたはＳであり；
Ｘは、でＯ、ＣＨ_２またはＣＤ_２であり；
Ｒ^５は、ＨまたはＤであり；
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^８およびＲ^９は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルから選択され；
Ｒ^１は、式：

or a pharma- ceutical acceptable salt thereof, wherein
U is O or S;
X is O, _CH2 or _CD2 ;
^R5 is H or D;
R ² , R ³ , R ⁴ , R ⁸ and R ⁹ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ¹⁰ ;
^R1 is a group represented by the formula:

の１つであり、
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
アリールは、フェニル、１－ナフチル、２－ナフチル、芳香族、複素芳香族、４－置換フェニル、４－クロロフェニル、４－ブロモフェニルであり；
Ｑは、少なくとも１つのチオン、チオールまたはチオエーテルで置換されている２個以上の窒素ヘテロ原子を含むヘテロシクリルであり、ここでＱは、１つ以上の同一であるまたは異なるアルキル、ハロゲン、シクロアルキルで置換されてもよく；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリル；から選択され；
Ｒ^６は、アルキル、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリールまたはヘテロシクリルであり、ここで各Ｒ^６は、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよい。

It is one of the
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl;
Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl;
Each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
^R6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl or heterocyclyl, where each ^R6 may be substituted with one or more identical or different ^R10 .

In a preferred embodiment, U is O and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine. In another preferred embodiment, U is S and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine.

In certain embodiments, ^R2 , ^R3 , ^R4 , ^R8 and ^R9 are each independently selected from H, D, _CH3 , CD3, _CF3 , _CF2H , _CFH2 , CH2OH, _CH2Cl , CCH, OH, _SH , _NH2 , _N3 , CHO, CN _, Cl, Br, F or I.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｕは、ＯまたはＳであり；
Ｒ^５は、ＨまたはＤであり；
Ｒ^１は、式：

or a pharma- ceutical acceptable salt thereof, wherein
U is O or S;
^R5 is H or D;
^R1 is a group represented by the formula:

の１つであり、
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり、
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
各Ｘは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
Ｒ^２は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^８、ＳＲ^８、ＮＨＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
ここで、式ＩｇおよびＩｈにおいて、ＸはＳであるもしくはＲ^２はＳＲ^８である一方、またはＸはＳであるおよびＲ^２はＳＲ^８である両方であり；
ここで、式Ｉｉにおいて、少なくとも１つのＸはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^８であり；
Ｚは、ＣＨ、ＮまたはＣＲ^８であり；
Ｒ^３、Ｒ^４、Ｒ^７、Ｒ^９およびＲ^１４は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
アリールは、フェニル、１－ナフチル、２－ナフチル、芳香族、複素芳香族、４－置換フェニル、４－クロロフェニル、４－ブロモフェニルであり；
Ｒ^８は、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
Ｒ^６は、アルキル、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリールまたはヘテロシクリルであり、ここで各Ｒ^６は、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよい。

It is one of the
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
Each X is independently O, S, NH, ^NR8 , NHOH, ^NR8OH , ^{NHOR8 , or NR8OR8 ;
R2} is OH, SH, _NH2 , ^OR8 , ^SR8 , ^NHR8 , NHOH, ^NR8OH , ^{NHOR8 or NR8OR8 ;}
wherein in formulae Ig and Ih, X is S or ^R2 is ^SR8 , or both X is S and ^R2 is ^SR8 ;
wherein in formula Ii, at least one X is S;
W is CH, N or ^CR8 ;
Z is CH, N or ^CR8 ;
R ³ , R ⁴ , R ⁷ , R ⁹ and R ¹⁴ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl;
R ⁸ is methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more identical or different R ¹⁰ ;
^R6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl or heterocyclyl, where each ^R6 may be substituted with one or more identical or different ^R10 .

In certain embodiments, U is S and Y and Z are CH.

In other embodiments, U is O and Y and Z are CH.

In one embodiment, R ⁵ is H. In another embodiment, R ³ is H. In yet another embodiment, R ⁴ is H. In yet another embodiment, R ⁷ is F and R ¹⁴ is H. In a further embodiment, R ¹ is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is H. In yet another embodiment, ^R7 is F and ^R14 is methyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, R ⁵ is H. In another embodiment, R ³ is H. In yet another embodiment, R ⁴ is H. In yet another embodiment, R ⁷ is F and R ¹⁴ is trifluoromethyl. In a further embodiment, R ¹ is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In yet another embodiment, ^R7 is F. In another embodiment, ^R14 is trifluoromethyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In yet another embodiment, ^R7 is F. In another embodiment, ^R14 is methyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is OH. In yet another embodiment, ^R7 is F and ^R14 is ethynyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is OH. In yet another embodiment, ^R7 is F and ^R14 is monofluoromethyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In yet another embodiment, ^R7 is H. In another embodiment, ^R14 is methyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is OH. In yet another embodiment, ^R7 is H and ^R14 is trifluoromethyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In yet another embodiment, ^R7 is hydroxyl. In another embodiment, ^R14 is trifluoromethyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In yet another embodiment, ^R7 is hydroxyl. In another embodiment, ^R14 is methyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In yet another embodiment, ^R7 is hydroxyl. In another embodiment, ^R14 is methyl. In a further embodiment, ^R1 is

であり、式中、ＹはＯである。

where Y is O.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In a more preferred embodiment, the compound of the present invention is:

の１つ以上から選択される。

is selected from one or more of:

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In yet another embodiment, ^R7 is hydroxyl. In another embodiment, ^R14 is ethynyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In yet another embodiment, ^R7 is hydroxyl. In another embodiment, ^R14 is monofluoromethyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is fluoro. In yet another embodiment, ^R7 is hydroxyl. In another embodiment, ^R14 is H. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is fluoro. In yet another embodiment, ^R7 is hydroxyl. In another embodiment, ^R14 is methyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is fluoro. In yet another embodiment, ^R7 is hydroxyl. In another embodiment, ^R14 is ethynyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is fluoro. In yet another embodiment, ^R7 is hydroxyl. In another embodiment, ^R14 is monofluoromethyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｅは、ＣＤ_２であり；
Ｕは、ＯまたはＳであり；
Ｒ^５は、ＨまたはＤであり；
Ｒ^１は、式：

or a pharma- ceutical acceptable salt thereof, wherein
E is _CD2 ;
U is O or S;
^R5 is H or D;
^R1 is a group represented by the formula:

の１つであり、
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり、
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
各Ｘは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
Ｒ^２は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^８、ＳＲ^８、ＮＨＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
ここで、式ＩｊおよびＩｋにおいて、Ｘの１つはＳであるもしくはＲ^２はＳＲ^８であり、またはＸはＳであるおよびＲ^２はＳＲ^８である両方であり；
ここで、式Ｉｌにおいて、少なくとも１つのＸはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^８であり；
Ｚは、ＣＨ、ＮまたはＣＲ^８であり；
Ｒ^３、Ｒ^４、Ｒ^７、Ｒ^９およびＲ^１４は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
アリールは、フェニル、１－ナフチル、２－ナフチル、芳香族、複素芳香族、４－置換フェニル、４－クロロフェニル、４－ブロモフェニルであり；
Ｒ^８は、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
Ｒ^６は、アルキル、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリールまたはヘテロシクリルであり、ここで各Ｒ^６は、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよい。

It is one of the
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
Each X is independently O, S, NH, ^NR8 , NHOH, ^NR8OH , ^{NHOR8 , or NR8OR8 ;
R2} is OH, SH, _NH2 , ^OR8 , ^SR8 , ^NHR8 , NHOH, ^NR8OH , ^{NHOR8 or NR8OR8 ;}
wherein in formulae Ij and Ik, one of X is S or ^R2 is ^SR8 , or both X is S and ^R2 is ^SR8 ;
wherein in formula II, at least one X is S;
W is CH, N or ^CR8 ;
Z is CH, N or ^CR8 ;
R ³ , R ⁴ , R ⁷ , R ⁹ and R ¹⁴ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl;
R ⁸ is methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more identical or different R ¹⁰ ;
^R6 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl or heterocyclyl, where each ^R6 may be substituted with one or more identical or different ^R10 .

In certain embodiments, U is S and Y and Z are CH.

In other embodiments, U is O and Y and Z are CH.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In yet another embodiment, ^R7 is hydroxyl. In another embodiment, ^R14 is methyl. In a further embodiment, ^R1 is

であり、式中、ＹはＯであり、Ｙ^１はフェノキシであり、Ｒ^６はｉｓｏ－プロピルである。

where Y is O, ^Y1 is phenoxy and ^R6 is iso-propyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In yet another embodiment, ^R7 is hydroxyl. In another embodiment, ^R14 is methyl. In a further embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１はＯ－アリールである。

where Y is O and ^Y1 is O-aryl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In a preferred embodiment, the nucleoside conjugated to the phosphorus moiety or a pharma- ceutical acceptable salt thereof has the following structure:

を有し、式中、
Ｒ_１は、以下：

wherein
_R1 is the following:

の１つから選択され、
Ｒ_４は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_５は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、または置換ヘテロアリールである。

is selected from one of
R ₄ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
_R5 is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, or substituted heteroaryl.

In an exemplary embodiment, the nucleoside conjugated to the phosphorus moiety or a pharma- ceutically acceptable salt thereof has the following structure:

を有する。

has.

In other embodiments, R ₁ of formula Im or In is:

の１つから選択され、式中、
Ｒ_２は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ_３は、アリール、ビアリールまたは置換アリールであり；
Ｒ_４は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_５は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、アルキニルまたは置換ヘテロアリールである。

wherein:
_R2 is alkyl, branched alkyl or cycloalkyl;
_R3 is aryl, biaryl or substituted aryl;
R ₄ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
_R5 is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, alkynyl or substituted heteroaryl.

In a preferred embodiment, the nucleoside conjugated to the phosphorus moiety or a pharma- ceutical acceptable salt thereof has the following structure:

を有し、
Ｒ_２は、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、分岐アルキル、またはシクロアルキルから選択され；
Ｒ_６は、脂質、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、分岐アルキル、ピバロイルオキシメチル、シクロアルキルであり、または

having
R ₂ is selected from C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, branched alkyl, or cycloalkyl;
_R6 is a lipid, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, branched alkyl, pivaloyloxymethyl, cycloalkyl, or

から選択され、
式中、Ｒ_４は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシである。

is selected from
wherein R ₄ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｕは、ＯまたはＳであり；
Ｘは、Ｏ、ＣＨ_２またはＣＤ_２であり；
Ｒ^５は、ＨまたはＤであり；
Ｑは、少なくとも１つのチオン、チオールまたはチオエーテルで置換されている２個以上の窒素ヘテロ原子を含むヘテロシクリルであり、ここでＱは、１つ以上の同一であるまたは異なるアルキル、ハロゲンまたはシクロアルキルで置換されてもよく；
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^８およびＲ^９は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
Ｒ^１は、式：

or a pharma- ceutical acceptable salt thereof, wherein
U is O or S;
X is O, _CH2 or _CD2 ;
^R5 is H or D;
Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl;
R ² , R ³ , R ⁴ , R ⁸ and R ⁹ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
^R1 is a group represented by the formula:

の１つであり、
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯＨまたはＢＨ_３－Ｍ^＋であり；
脂質は、本明細書に記載されている通りである。

It is one of the
Y is O or S;
^Y1 is OH or _BH3 -M ⁺ ;
The lipids are as described herein.

In certain embodiments, Q heterocyclyl is selected from pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

In a preferred embodiment, U is O and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine. In another preferred embodiment, U is S and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｒ^５は、ＨまたはＤであり；
Ｕは、ＯまたはＳであり；
Ｅは、ＣＨ_２またはＣＤ_２であり；
Ｒ^１は、式：

or a pharma- ceutical acceptable salt thereof, wherein
^R5 is H or D;
U is O or S;
E is _CH2 or _CD2 ;
^R1 is a group represented by the formula:

の１つであり、
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯＨまたはＢＨ_３－Ｍ^＋であり；
脂質は、本明細書に記載されている通りであり；
各Ｘは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
Ｒ^２は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^８、ＳＲ^８、ＮＨＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
ここで、式ＩｐおよびＩｑにおいて、ＸはＳであるもしくはＲ^２はＳＲ^８である一方、またはＸはＳであるおよびＲ^２はＳＲ^８である両方であり；
ここで、式Ｉｒにおいて、少なくとも１つのＸはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^８であり；
Ｚは、ＣＨ、ＮまたはＣＲ^８であり；
Ｒ^８は、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
Ｒ^３、Ｒ^４、Ｒ^６、Ｒ^７およびＲ^１４は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択される。

It is one of the
Y is O or S;
^Y1 is OH or _BH3 -M ⁺ ;
The lipid is as described herein;
Each X is independently O, S, NH, ^NR8 , NHOH, ^NR8OH , ^{NHOR8 , or NR8OR8 ;
R2} is OH, SH, _NH2 , ^OR8 , ^SR8 , ^NHR8 , NHOH, ^NR8OH , ^{NHOR8 or NR8OR8 ;}
wherein in formulae Ip and Iq, X is S or ^R2 is ^SR8 , or both X is S and ^R2 is ^SR8 ;
wherein in formula Ir, at least one X is S;
W is CH, N or ^CR8 ;
Z is CH, N or ^CR8 ;
R ⁸ is methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more identical or different R ¹⁰ ;
R ³ , R ⁴ , R ⁶ , R ⁷ and R ¹⁴ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more of the same or different R ¹⁰ ;
Each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) ₂ amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, U is S and Y and Z are CH.

In other embodiments, U is O and Y and Z are CH.

In certain embodiments, the lipid has the formula:

を有するスフィンゴ脂質であり、式中、
スフィンゴ脂質のＲ^８は、水素、アルキル、Ｃ（＝Ｏ）Ｒ^１２、Ｃ（＝Ｏ）ＯＲ^１２またはＣ（＝Ｏ）ＮＨＲ^１２であり；
スフィンゴ脂質のＲ^９は、水素、フルオロ、ＯＲ^１２、ＯＣ（＝Ｏ）Ｒ^１２、ＯＣ（＝Ｏ）ＯＲ^１２またはＯＣ（＝Ｏ）ＮＨＲ^１２であり；
スフィンゴ脂質のＲ^１０は、１つ以上のハロゲンもしくはヒドロキシで置換されてもよい６個超および２２個未満の炭素の飽和もしくは不飽和アルキル鎖、または以下の式：

A sphingolipid having the formula:
R ⁸ of the sphingolipid is hydrogen, alkyl, C(═O)R ¹² , C(═O)OR ¹² or C(═O)NHR ¹² ;
R ⁹ of the sphingolipid is hydrogen, fluoro, OR ¹² , OC(═O)R ¹² , OC(═O)OR ¹² or OC(═O)NHR ¹² ;
R ¹⁰ of the sphingolipid is a saturated or unsaturated alkyl chain of more than 6 and less than 22 carbons, which may be substituted with one or more halogens or hydroxy, or a group represented by the following formula:

（ｎは、８から１４もしくは８以下から１４以下であり、ｏは、９から１５もしくは９以下から１５以下であり、ｍおよびｎの合計は、８から１４もしくは８以下から１４以下であり、ｍおよびｏの合計は、９から１５もしくは９以下から１５以下である。）；もしくは

wherein n is from 8 to 14 or from 8 to 14 inclusive, o is from 9 to 15 or from 9 to 15 inclusive, the sum of m and n is from 8 to 14 or from 8 to 14 inclusive, and the sum of m and o is from 9 to 15 or from 9 to 15 inclusive; or

（ｎは、４から１０もしくは４以下から１０以下であり、ｏは、５から１１もしくは５以下から１１以下であり、ｍおよびｎの合計は、４から１０もしくは４以下から１０以下であり、ｍおよびｏの合計は、５から１１もしくは５以下から１１以下である。）；もしくは

wherein n is 4 to 10 or 4 or less to 10 or less, o is 5 to 11 or 5 or less to 11 or less, the sum of m and n is 4 to 10 or 4 or less to 10 or less, and the sum of m and o is 5 to 11 or 5 or less to 11 or less; or

（ｎは、６から１２もしくは６以下から１２以下であり、ｍおよびｎの合計は、６から１２であるもしくはｎは６以下から１２以下である。）
の構造であり；
スフィンゴ脂質のＲ^１１は、ＯＲ^１２、ＯＣ（＝Ｏ）Ｒ^１２、ＯＣ（＝Ｏ）ＯＲ^１２またはＯＣ（＝Ｏ）ＮＨＲ^１２であり；
スフィンゴ脂質のＲ^１２は、水素、分岐もしくは直鎖Ｃ_１－１２アルキル、Ｃ_{１３－２２}アルキル、シクロアルキル、またはベンジルもしくはフェニルから選択されるアリールであり、ここで、アリールは、１つ以上の同一であるまたは異なるＲ^１３で置換されてもよく；
スフィンゴ脂質のＲ^１３は、ハロゲン、ニトロ、シアノ、ヒドロキシ、トリフルオロメトキシ、トリフルオロメチル、アミノ、ホルミル、カルボキシ、カルバモイル、メルカプト、スルファモイル、メチル、エチル、メトキシ、エトキシ、アセチル、アセトキシ、メチルアミノ、エチルアミノ、ジメチルアミノ、ジエチルアミノ、Ｎ－メチル－Ｎ－エチルアミノ、アセチルアミノ、Ｎ－メチルカルバモイル、Ｎ－エチルカルバモイル、Ｎ，Ｎ－ジメチルカルバモイル、Ｎ，Ｎ－ジエチルカルバモイル、Ｎ－メチル－Ｎ－エチルカルバモイル、メチルチオ、エチルチオ、メチルスルフィニル、エチルスルフィニル、メシル、エチルスルホニル、メトキシカルボニル、エトキシカルボニル、Ｎ－メチルスルファモイル、Ｎ－エチルスルファモイル、Ｎ，Ｎ－ジメチルスルファモイル、Ｎ，Ｎ－ジエチルスルファモイル、Ｎ－メチル－Ｎ－エチルスルファモイル、カルボシクリル、アリール、またはヘテロシクリルである。

(n is 6 to 12 or 6 or less to 12 or less, and the sum of m and n is 6 to 12 or n is 6 or less to 12 or less.)
The structure is
R ¹¹ of the sphingolipid is OR ¹² , OC(═O)R ¹² , OC(═O)OR ¹² or OC(═O)NHR ¹² ;
R ¹² of the sphingolipid is hydrogen, branched or straight chain C _1-12 alkyl, C _13-22 alkyl, cycloalkyl, or aryl selected from benzyl or phenyl, where the aryl is optionally substituted with one or more identical or different R ¹³ ;
R ¹³ of the sphingolipid is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, R ¹² of the sphingolipid is H, alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenyl, mono-substituted phenyl, di-substituted phenyl, tri-substituted phenyl, or saturated or unsaturated C12-C19 long chain alkyl.

In certain embodiments, the sphingolipid has the formula:

を有し、式中、
スフィンゴ脂質のＲ^８は、水素、ヒドロキシ、フルオロ、ＯＲ^１２、ＯＣ（＝Ｏ）Ｒ^１２、ＯＣ（＝Ｏ）ＯＲ^１２またはＯＣ（＝Ｏ）ＮＨＲ^１２であり；
スフィンゴ脂質のＲ^９は、水素、ヒドロキシ、フルオロ、ＯＲ^１２、ＯＣ（＝Ｏ）Ｒ^１２、ＯＣ（＝Ｏ）ＯＲ^１２またはＯＣ（＝Ｏ）ＮＨＲ^１２であり；
スフィンゴ脂質のＲ^１０は、１つ以上のハロゲンで置換されてもよい６個超および２２個未満の炭素の飽和もしくは不飽和アルキル鎖、または以下の式：

wherein
R ⁸ of the sphingolipid is hydrogen, hydroxy, fluoro, OR ¹² , OC(═O)R ¹² , OC(═O)OR ¹² or OC(═O)NHR ¹² ;
R ⁹ of the sphingolipid is hydrogen, hydroxy, fluoro, OR ¹² , OC(═O)R ¹² , OC(═O)OR ¹² or OC(═O)NHR ¹² ;
R ¹⁰ of the sphingolipid is a saturated or unsaturated alkyl chain of more than 6 and less than 22 carbons, optionally substituted with one or more halogens, or a group represented by the following formula:

（ｎは、８から１４もしくは８以下から１４以下であり、ｍおよびｎの合計は、８から１４もしくは８以下から１４以下である。）
の構造であり；
スフィンゴ脂質のＲ^１２は、水素、分岐または直鎖Ｃ_１－１２アルキル、Ｃ_{１３－２２}アルキル、シクロアルキル、またはベンジルもしくはフェニルから選択されるアリールであり、ここでアリールは、１つ以上の同一であるまたは異なるＲ^１３で置換されてもよく；
スフィンゴ脂質のＲ^１３は、ハロゲン、ニトロ、シアノ、ヒドロキシ、トリフルオロメトキシ、トリフルオロメチル、アミノ、ホルミル、カルボキシ、カルバモイル、メルカプト、スルファモイル、メチル、エチル、メトキシ、エトキシ、アセチル、アセトキシ、メチルアミノ、エチルアミノ、ジメチルアミノ、ジエチルアミノ、Ｎ－メチル－Ｎ－エチルアミノ、アセチルアミノ、Ｎ－メチルカルバモイル、Ｎ－エチルカルバモイル、Ｎ，Ｎ－ジメチルカルバモイル、Ｎ，Ｎ－ジエチルカルバモイル、Ｎ－メチル－Ｎ－エチルカルバモイル、メチルチオ、エチルチオ、メチルスルフィニル、エチルスルフィニル、メシル、エチルスルホニル、メトキシカルボニル、エトキシカルボニル、Ｎ－メチルスルファモイル、Ｎ－エチルスルファモイル、Ｎ，Ｎ－ジメチルスルファモイル、Ｎ，Ｎ－ジエチルスルファモイル、Ｎ－メチル－Ｎ－エチルスルファモイル、カルボシクリル、アリール、またはヘテロシクリルである。

(n is 8 to 14 or 8 or less to 14 or less, and the sum of m and n is 8 to 14 or 8 or less to 14 or less).
The structure is
R ¹² of the sphingolipid is hydrogen, branched or straight chain C _1-12 alkyl, C _13-22 alkyl, cycloalkyl, or aryl selected from benzyl or phenyl, where the aryl is optionally substituted with one or more identical or different R ¹³ ;
R ¹³ of the sphingolipid is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, R ¹² of the sphingolipid is H, alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenyl, monosubstituted phenyl, disubstituted phenyl, trisubstituted phenyl, or saturated or unsaturated C ₁₂ -C ₁₉ long chain alkyl.

In one embodiment, ^R5 is H. In another embodiment, ^R4 is hydroxyl. In yet another embodiment, ^R7 is hydroxyl. In yet another embodiment, ^R14 is methyl. In a further embodiment, ^R3 is hydrogen. In another embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１は－ＯＨであり、脂質はスフィンゴ脂質である。別の実施形態において、ＥはＣＨ_２である。例示的な実施形態において、該化合物は、

wherein Y is O, ^Y1 is -OH and the lipid is a sphingolipid. In another embodiment, E is _CH2 . In an exemplary embodiment, the compound is

から選択される。

is selected from.

In one embodiment, ^R5 is H. In another embodiment, ^R4 is hydroxyl. In yet another embodiment, ^R7 is hydroxyl. In yet another embodiment, ^R14 is methyl. In a further embodiment, ^R3 is hydrogen. In another embodiment, ^R1 is

であり、ここでＹはＯであり、Ｙ^１は－ＯＨであり、脂質はスフィンゴ脂質である。別の実施形態において、ＥはＣＤ_２である。例示的な実施形態において、該化合物は、

wherein Y is O, ^Y1 is -OH and the lipid is a sphingolipid. In another embodiment, E is _CD2 . In an exemplary embodiment, the compound is

から選択される。

is selected from.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｕは、ＯまたはＳであり；
Ｘは、ＣＨ_２またはＣＤ_２であり；
Ｒ^５は、ＨまたはＤであり；
Ｒ^１は、ヒドロキシルであり；
Ｑは、少なくとも１つのチオン、チオールまたはチオエーテルで置換されている２個以上の窒素ヘテロ原子を含むヘテロシクリルであり、ここでＱは、１つ以上の同一であるまたは異なるアルキル、ハロゲン、またはシクロアルキルで置換されてもよく；
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^８およびＲ^９は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択される。

or a pharma- ceutical acceptable salt thereof, wherein
U is O or S;
X is _CH2 or _CD2 ;
^R5 is H or D;
^R1 is hydroxyl;
Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl;
R ² , R ³ , R ⁴ , R ⁸ and R ⁹ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ¹⁰ ;
Each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) ₂ amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, Q heterocyclyl is selected from pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

In a preferred embodiment, U is O and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine. In another preferred embodiment, U is S and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine.

In certain embodiments, R ⁸ and R ⁹ are selected from H, fluoro, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl, and cyano.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこれらの医薬として許容される塩に関し、
Ｒ^５は、ＨまたはＤであり；
Ｕは、ＯまたはＳであり；
各Ｘは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
Ｒ^１は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^８、ＳＲ^８、ＮＨＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
ここで、式ＩｔおよびＩｕにおいて、ＸがＳであるもしくはＲ^１がＳＲ^８である一方、またはＸがＳであるおよびＲ^１がＳＲ^８である両方であり；
ここで、式Ｉｖにおいて、少なくとも１つのＸはＳであり；
Ｙは、ＣＨ、ＮまたはＣＲ^８であり；
Ｚは、ＣＨ、ＮまたはＣＲ^８であり；
Ｒ^７およびＲ^１４は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^８は、独立して、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択される。

or a pharma- ceutical acceptable salt thereof,
^R5 is H or D;
U is O or S;
Each X is independently O, S, NH, ^NR8 , NHOH, ^NR8OH , ^{NHOR8 , or NR8OR8 ;
R1} is OH, SH, _NH2 , ^OR8 , ^SR8 , ^NHR8 , NHOH, ^NR8OH , ^{NHOR8 or NR8OR8 ;}
wherein in formula It and Iu, X is S or R ¹ is SR ⁸ , or both X is S and R ¹ is SR ⁸ ;
wherein in formula Iv, at least one X is S;
Y is CH, N or ^CR8 ;
Z is CH, N or ^CR8 ;
R ⁷ and R ¹⁴ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more of the same or different R ¹⁰ ;
Each R ⁸ is independently selected from methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more of the same or different R ¹⁰ ;
Each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) ₂ amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, U is S and Y and Z are CH.

In other embodiments, U is O and Y and Z are CH.

In certain embodiments, R ⁵ is H. In other embodiments, R ⁷ is F and R ¹⁴ is H. In an exemplary embodiment, the compound is

から選択される。

is selected from.

In certain embodiments, R ⁵ is H. In other embodiments, R ⁷ is F and R ¹⁴ is methyl. In an exemplary embodiment, the compound is

から選択される。

is selected from.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこれらの医薬として許容される塩に関し、式中、
Ｕは、ＯまたはＳであり；
Ｑは、少なくとも１つのチオン、チオールまたはチオエーテルで置換されている２個以上の窒素ヘテロ原子を含むヘテロシクリルであり、ここでＱは、１つ以上の同一であるまたは異なるアルキル、ハロゲン、シクロアルキルで置換されてもよく；
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^６およびＲ^７は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^９で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^９は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
Ｒ^５はＨまたはＤである。

or a pharma- ceutical acceptable salt thereof, wherein
U is O or S;
Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl;
R ² , R ³ , R ⁴ , R ⁶ and R ⁷ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ⁹ ;
Each ^R9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
^R5 is H or D.

In certain embodiments, Q heterocyclyl is selected from pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

In a preferred embodiment, U is O and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine. In another preferred embodiment, U is S and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine.

In certain embodiments, the disclosure provides a compound of the formula:

の１つの化合物またはこれらの医薬として許容される塩に関し、式中、
Ｕは、ＯまたはＳであり；
Ｒ^５は、ＨまたはＤであり；
各Ｘは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
Ｒ^１は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^８、ＳＲ^８、ＮＨＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
ここで、式ＩｘおよびＩｙにおいて、ＸがＳであるもしくはＲ^１がＳＲ^８である一方、またはＸがＳであるおよびＲ^１がＳＲ^８である両方であり；
ここで、式Ｉｚにおいて、少なくとも１つのＸはＳであり；
Ｙは、ＣＨ、ＮまたはＣＲ^８であり；
Ｚは、ＣＨ、ＮまたはＣＲ^８であり；
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^６およびＲ^７は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^９で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^８は、独立して、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^９で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^９は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択される。

or a pharma- ceutically acceptable salt thereof, wherein
U is O or S;
^R5 is H or D;
Each X is independently O, S, NH, ^NR8 , NHOH, ^NR8OH , ^{NHOR8 , or NR8OR8 ;
R1} is OH, SH, _NH2 , ^OR8 , ^SR8 , ^NHR8 , NHOH, ^NR8OH , ^{NHOR8 or NR8OR8 ;}
wherein in formula Ix and Iy, X is S or R ¹ is SR ⁸ , or both X is S and R ¹ is SR ⁸ ;
wherein in formula Iz, at least one X is S;
Y is CH, N or ^CR8 ;
Z is CH, N or ^CR8 ;
R ² , R ³ , R ⁴ , R ⁶ and R ⁷ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ⁹ ;
Each R ⁸ is independently selected from methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more identical or different R ⁹ ;
Each ^R9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, U is S and Y and Z are CH.

In other embodiments, U is O and Y and Z are CH.

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is methyl. In yet a further embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is trifluoromethyl. In yet a further embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is C≡CH. In yet a further embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is _CH2F . In yet another embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is H. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is H. In yet a further embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is H. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is methyl. In yet a further embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is H. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is trifluoromethyl. In yet a further embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is methyl. In yet a further embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is trifluoromethyl. In yet a further embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is C≡CH. In yet a further embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is _CH2F . In yet a further embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is methyl. In a still further embodiment, ^R7 is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is trifluoromethyl. In a still further embodiment, ^R7 is H. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is _N3 . In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is H. In yet a further embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is C≡CH. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is H. In yet a further embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is _CH2F . In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is H. In yet a further embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is _N3 . In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is H. In yet a further embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is C≡CH. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is H. In yet a further embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is _CH2F . In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is H. In yet a further embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is fluoro. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is H. In yet a further embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is fluoro. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is methyl. In yet a further embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is fluoro. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is C≡CH. In yet a further embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is H. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is fluoro. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is _CH2F . In yet a further embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is fluoro. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is methyl. In yet another embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is fluoro. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is C≡CH. In yet a further embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is fluoro. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is _CH2F . In yet a further embodiment, ^R7 is hydroxyl. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is fluoro. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is methyl. In yet a further embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is fluoro. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is C≡CH. In yet a further embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, ^R2 is fluoro. In another embodiment, ^R3 is H. In yet another embodiment, ^R4 is hydroxyl. In a further embodiment, ^R5 is H. In yet another embodiment, ^R6 is _CH2F . In yet a further embodiment, ^R7 is fluoro. In an exemplary embodiment, the compound is

からなる群から選択される。

is selected from the group consisting of:

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートであり、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
^R1 is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｕは、ＯまたはＳであり；
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^７は、Ｈ、Ｄ、Ｎ_３、エチニル、ビニル、フルオロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、メチル、ＣＤ_３、ヒドロキシメチルまたはシアノであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチルまたはビニルであり；
Ｒ^４は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^６は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチルまたはビニルである。

is selected from one of
U is O or S;
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
R ⁷ is H, D, N ₃ , ethynyl, vinyl, fluoro, fluoromethyl, difluoromethyl, trifluoromethyl, methyl, CD ₃ , hydroxymethyl or cyano;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl or vinyl;
^R4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R6 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl or vinyl.

In certain embodiments, U is S and Z is CH.

In other embodiments, U is O and Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートであり、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
^R1 is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^４は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^６は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R6 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^４は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^６は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R6 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.

In certain embodiments, Z is CH.

In a preferred embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^４は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^６は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R6 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^４は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^６は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R6 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^４は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^６は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R6 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^６は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R6 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^６は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R6 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^６は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R6 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^６は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R6 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^４は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^４は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^４は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^４は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein:
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^４は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

の化合物またはこれらの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートである、または以下：

or a pharma- ceutical acceptable salt thereof, wherein
R ¹ is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ^３’は、アリール、ビアリールまたは置換アリールであり；
Ｚは、ＣＨまたはＮであり；
Ｒ^３は、Ｈ、Ｄ、メチル、ＣＤ_３、エチニル、シアノ、フルオロ、クロロ、フルオロメチル、ジフルオロメチル、トリフルオロメチル、ヒドロキシメチル、ビニルまたはアリルであり；
Ｒ^４は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨであり；
Ｒ^５は、Ｈ、Ｄ、ヒドロキシル、メトキシ、アジド、アミノ、フルオロ、クロロまたはＳＨである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ³ ' is aryl, biaryl or substituted aryl;
Z is CH or N;
^R3 is H, D, methyl, _CD3 , ethynyl, cyano, fluoro, chloro, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, vinyl or allyl;
^R4 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH;
^R5 is H, D, hydroxyl, methoxy, azido, amino, fluoro, chloro or SH.

In certain embodiments, Z is CH.

In one embodiment, the nucleoside conjugated to the phosphorus moiety has the following formula:

の化合物またはこの医薬として許容される塩であり、式中、
Ｒ^１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートであり、または以下：

or a pharma- ceutical acceptable salt thereof, wherein
^R1 is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され、
Ｒ^２’は、アルキル、分岐アルキルまたはシクロアルキルであり、
Ｒ^３’は、アリール、ビアリールまたは置換アリールである。

is selected from one of
R ^2′ is alkyl, branched alkyl or cycloalkyl;
R ^3' is aryl, biaryl or substituted aryl.

In another embodiment, R ¹ is:

の１つから選択され、
Ｒ_４は、アルキル、分岐アルキル、シクロアルキルまたはアルキオキシであり；
Ｒ_５は、アリール、ヘテロアリール、置換アリールまたは置換ヘテロアリールである。

is selected from one of
_R4 is alkyl, branched alkyl, cycloalkyl or alkyoxy;
_R5 is aryl, heteroaryl, substituted aryl or substituted heteroaryl.

In certain embodiments of formula I, X is methylene (CH ₂ ) and R ¹ is:

の１つであり、
式中、Ｒ^１２は、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、分岐アルキル、またはシクロアルキルであり；Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯＨ、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
アリールは、フェニル、１－ナフチル、２－ナフチル、芳香族、複素芳香族、４－置換フェニル、４－クロロフェニル、４－ブロモフェニルである。

It is one of the
wherein R ¹² is C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, branched alkyl, or cycloalkyl; Y is O or S;
^Y1 is OH, Oaryl or _BH3 ^- M ⁺ ;
Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl.

In certain embodiments, X is methylene (CH ₂ ) and R ¹ is:

の１つであり、式中、
Ｙは、ΟまたはＳであり；
Ｙ^１は、ＯＨ、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
アリールは、フェニル、１－ナフチル、２－ナフチル、芳香族、複素芳香族、４－置換フェニル、４－クロロフェニル、４－ブロモフェニルである。

is one of the formulas:
Y is O or S;
^Y1 is OH, Oaryl or _BH3 ^- M ⁺ ;
Aryl is phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-chlorophenyl, 4-bromophenyl.

In a particular embodiment, the present invention provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｕは、ＯまたはＳであり；
Ｙ^２は、ＯまたはＳであり；
Ｙ^３は、ＯＲ^１０、脂質、ＢＨ_３－Ｍ^＋であり、または

or a pharma- ceutical acceptable salt thereof, wherein
U is O or S;
^Y2 is O or S;
^Y3 is OR ¹⁰ , a lipid, BH ₃ -M ⁺ , or

から選択され；
Ｅは、ＣＨ_２またはＣＤ_２であり；
Ｒ^５は、ＨまたはＤであり；
Ｑは、少なくとも１つのチオン、チオールまたはチオエーテルで置換されている２個以上の窒素ヘテロ原子を含むヘテロシクリルであり、ここでＱは、１つ以上の同一であるまたは異なるアルキル、ハロゲン、シクロアルキルで置換されてもよく；
Ｒ^２、Ｒ^３、Ｒ^６およびＲ^７は、独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^１１で置換されてもよいＣ_１－２２アルキルから選択され；
Ｒ^１０は、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、分岐アルキルまたはシクロアルキルであり；
Ｒ^４は、Ｃ_１－２２アルキル、Ｃ_１－２２アルコキシ、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、分岐アルキルまたはシクロアルキルであり；
各Ｒ^１１は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択される。

Selected from:
E is _CH2 or _CD2 ;
^R5 is H or D;
Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl;
R ² , R ³ , R ⁶ and R ⁷ are independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ¹¹ ;
R ¹⁰ is C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, branched alkyl or cycloalkyl;
R ⁴ is C _1-22 alkyl, C _1-22 alkoxy, C _2-22 alkenyl, C _2-22 alkynyl, branched alkyl or cycloalkyl;
Each R ¹¹ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) ₂ amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, Q heterocyclyl is selected from pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

In a preferred embodiment, U is O and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine. In another preferred embodiment, U is S and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine.

In certain other embodiments, ^R2 , ^R3 , ^R6 and ^R7 are independently selected from the group consisting of H, D, _CH3 , CD3, _CF3 , _CF2H , _CFH2 , OH, SH, _NH2 , _N3 , CHO, _CN , Cl, Br, F or I.

In yet other certain embodiments, R ¹⁰ is alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-butyl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物に関し、
Ｕは、ＯまたはＳであり；
ここで、Ｒ_１およびＲ_２は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^８で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^８は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され、
Ｑは、

With respect to the compound
U is O or S;
wherein R ₁ and R ₂ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ⁸ ;
each ^R8 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
Q is,

から選択され；
Ｙは、ＯまたはＳであり；
Ｒは、直鎖または分岐アルキル、例えばメチル、エチル、プロピル、ｎ－ブチル、イソプロピル、２－ブチル、１－エチルプロピル、１－プロピルブチルもしくはＣ_{１２－１９}長鎖アルキル；シクロアルキル、例えばシクロプロピル、シクロブチル、シクロペンチルもしくはシクロヘキシル；またはベンジルである。

Selected from:
Y is O or S;
R is a straight or branched alkyl, such as methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl or a C _12-19 long chain alkyl; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or benzyl.

In certain embodiments, the disclosure provides a compound of formula:

の化合物またはこれらの医薬として許容される塩に関し、式中、
Ｕは、ＯまたはＳであり；
ここで、Ｒ_１およびＲ_９は、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
Ｑは、

or a pharma- ceutical acceptable salt thereof, wherein
U is O or S;
wherein R ₁ and R ₉ are selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
Q is,

から選択され；
Ｙは、ＯまたはＳであり；
脂質は、

Selected from:
Y is O or S;
Lipids are

であり；
式中、Ｒ_２は、Ｈ；アルキル、例えばメチル；Ｃ（Ｏ）Ｒ’；Ｃ（Ｏ）ＯＲ’；またはＣ（Ｏ）ＮＨＲ’であり；
Ｒ_３は、Ｈ；ヒドロキシル；フルオロ；ＯＲ’；ＯＣ（Ｏ）Ｒ’；ＯＣ（Ｏ）ＯＲ’；ＯＣ（Ｏ）ＮＨＲ’であり；
Ｒ’は、Ｈ；直鎖または分岐のアルキル、例えばメチル、エチル、プロピル、ｎ－ブチル、イソプロピル、２－ブチル、１－エチルプロピル、１－プロピルブチル、またはＣ_{１２－１９}長鎖アルキル；シクロアルキル、例えばシクロプロピル、シクロブチル、シクロペンチルまたはシクロヘキシル；ベンジル；フェニル；一置換フェニル；二置換フェニルまたは三置換フェニルであり；
Ｒ_４は、Ｃ_{１１－１７}長アルキル鎖、例えば、

and
where _R2 is H; alkyl, e.g., methyl; C(O)R';C(O)OR'; or C(O)NHR';
_R3 is H; hydroxyl; fluoro; OR';OC(O)R';OC(O)OR';OC(O)NHR';
R' is H; straight or branched alkyl, such as methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, or a C _12-19 long chain alkyl; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; benzyl; phenyl; mono-substituted phenyl; di-substituted phenyl, or tri-substituted phenyl;
_R4 is a C _11-17 long alkyl chain, for example:

（式中、ｎは８－１４であり、ｏは９－１５である。）；または

where n is 8-14 and o is 9-15; or

（式中、「ｍ＋ｎ」は８－１４であり、「ｍ＋ｏ」は９－１５である。）：または

(wherein "m+n" is 8-14 and "m+o" is 9-15): or

（式中、ｎは４－１０であり、ｏは５－１１である。）；または

where n is 4-10 and o is 5-11; or

（式中、「ｍ＋ｎ」は４－１０であり、「ｍ＋ｏ」は５－１１である。）；または

where "m+n" is 4-10 and "m+o" is 5-11; or

（式中、ｎは６－１２である。）；または

where n is 6-12; or

（式中、「ｍ＋ｎ」は６－１２である。）
であり；
Ｒ_５は、Ｈ、ヒドロキシル、フルオロ、ＯＲ’、ＯＣ（Ｏ）Ｒ’、ＯＣ（Ｏ）ＯＲ’またはＯＣ（Ｏ）ＮＨＲ’である。

(In the formula, “m+n” is 6-12.)
and
_R5 is H, hydroxyl, fluoro, OR', OC(O)R', OC(O)OR' or OC(O)NHR'.

In an alternative embodiment, the lipid is

であり；
式中、Ｒ_６は、Ｈ；ヒドロキシル；フルオロ；ＯＲ’；ＯＣ（Ｏ）Ｒ’；ＯＣ（Ｏ）ＯＲ’；またはＯＣ（Ｏ）ＮＨＲ’であり；
Ｒ^７は、Ｈ；ヒドロキシル；フルオロ；ＯＲ’；ＯＣ（Ｏ）Ｒ’；ＯＣ（Ｏ）ＯＲ’；またはＯＣ（Ｏ）ＮＨＲ’であり；
Ｒ’は、Ｈ；直鎖または分岐のアルキル、例えばメチル、エチル、プロピル、ｎ－ブチル、イソプロピル、２－ブチル、１－エチルプロピル、１－プロピルブチル、またはＣ_{１２－１９}長鎖アルキル；シクロアルキル、例えばシクロプロピル、シクロブチル、シクロペンチルまたはシクロヘキシル；ベンジル；フェニル；一置換フェニル；二置換フェニル；三置換フェニルであり；
Ｒ_８は、Ｃ_９－１５アルキル鎖、例えば

and
wherein R ₆ is H; hydroxyl; fluoro; OR′; OC(O)R′; OC(O)OR′; or OC(O)NHR′;
^R7 is H; hydroxyl; fluoro; OR';OC(O)R';OC(O)OR'; or OC(O)NHR';
R' is H; straight or branched alkyl, such as methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, or a C _12-19 long chain alkyl; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; benzyl; phenyl; monosubstituted phenyl; disubstituted phenyl; trisubstituted phenyl;
R ₈ is a C _9-15 alkyl chain, e.g.

（式中、ｎは８－１４である。）または

where n is 8-14; or

（式中、「ｍ＋ｎ」は８－１４である。）である。

(wherein “m+n” is 8-14.)

In certain embodiments, the disclosure provides a compound of formula:

の化合物またはこれらの医薬として許容される塩に関し、式中、
Ｒ^５は、ＨまたはＤであり；
Ｅは、ＣＨ_２またはＣＤ_２であり；
Ｕは、ＯまたはＳであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯＲ^４０、脂質、ＢＨ_３－Ｍ^＋であり、または

or a pharma- ceutical acceptable salt thereof, wherein
^R5 is H or D;
E is _CH2 or _CD2 ;
U is O or S;
Y is O or S;
Y ¹ is OR ⁴⁰ , a lipid, BH ₃ -M ⁺ , or

から選択され；
各Ｘは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
Ｒ^１は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^８、ＳＲ^８、ＮＨＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
ここで、式ＩＩｃおよびＩＩｄにおいて、ＸがＳであるもしくはＲ^１がＳＲ^８である一方、またはＸがＳであるおよびＲ^１がＳＲ^８である両方であり；
ここで、式ＩＩｅにおいて、少なくとも１つのＸはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^８であり；
Ｚは、ＣＨ、ＮまたはＣＲ^８であり；
Ｒ^６、Ｒ^７およびＲ^９は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^８で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^８は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリールまたはヘテロシクリルから選択され；
Ｒ^４０は、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、分岐アルキル、シクロアルキルであり；
Ｒ^４は、Ｃ_１－２２アルキル、Ｃ_１－２２アルコキシ、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、分岐アルキル、シクロアルキルである。

Selected from:
Each X is independently O, S, NH, ^NR8 , NHOH, ^NR8OH , ^{NHOR8 , or NR8OR8 ;
R1} is OH, SH, _NH2 , ^OR8 , ^SR8 , ^NHR8 , NHOH, ^NR8OH , ^{NHOR8 or NR8OR8 ;}
wherein in formula IIc and IId, X is S or R ¹ is SR ⁸ , or both X is S and R ¹ is SR ⁸ ;
wherein in formula IIe, at least one X is S;
W is CH, N or ^CR8 ;
Z is CH, N or ^CR8 ;
R ⁶ , R ⁷ and R ⁹ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ⁸ ;
Each ^R8 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
R ⁴⁰ is C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, branched alkyl, cycloalkyl;
^R4 is C _1-22 alkyl, C _1-22 alkoxy, C _2-22 alkenyl, C _2-22 alkynyl, branched alkyl, cycloalkyl.

In certain embodiments, U is S and Y and Z are CH.

In other embodiments, U is O and Y and Z are CH.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In a particular embodiment, the present invention provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｒ^５は、ＨまたはＤであり；
Ｕは、ＯまたはＳであり；
Ｅは、ＣＨ_２またはＣＤ_２であり；
Ｙ^２は、ＯまたはＳであり；
Ｒ^２、Ｒ^３、Ｒ^６およびＲ^７は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^８で置換されてもよいＣ_１－２２アルキルから選択され；
Ｑは、少なくとも１つのチオン、チオールまたはチオエーテルで置換されている２個以上の窒素ヘテロ原子を含むヘテロシクリルであり、ここでＱは、１つ以上の同一であるまたは異なるアルキル、ハロゲンまたはシクロアルキルで置換されてもよく；
各Ｒ^８は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
Ｒ^１９は、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、分岐アルキル、シクロアルキルである。

or a pharma- ceutical acceptable salt thereof, wherein
^R5 is H or D;
U is O or S;
E is _CH2 or _CD2 ;
^Y2 is O or S;
R ² , R ³ , R ⁶ and R ⁷ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ⁸ ;
Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl;
Each ^R8 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
R ¹⁹ is C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, branched alkyl, cycloalkyl.

In a preferred embodiment, U is O and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine. In another preferred embodiment, U is S and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine.

In certain embodiments, R ⁶ is selected from hydrogen, methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, acetylenyl, ethyl, vinyl, or cyano.

In certain embodiments, R ¹⁹ is selected from alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-butyl.

In certain embodiments, the disclosure provides a compound of formula:

の化合物またはこれらの医薬として許容される塩に関し、式中、
Ｕは、ＯまたはＳであり；
Ｒ^６およびＲ^７は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルから選択され；
各Ｒ^１１は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
Ｑは、

or a pharma- ceutical acceptable salt thereof, wherein
U is O or S;
R ⁶ and R ⁷ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more of the same or different R ¹⁰ ;
Each R ¹¹ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) ₂ amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
Q is,

から選択され；
Ｙは、ＯまたはＳであり；
Ｒは、直鎖または分岐のアルキル、例えばメチル、エチル、プロピル、ｎ－ブチル、イソプロピル、２－ブチル、１－エチルプロピル、１－プロピルブチル、またはＣ_{１２－１９}長鎖アルキル；シクロアルキル、例えばシクロプロピル、シクロブチル、シクロペンチルもしくはシクロヘキシル；またはベンジルである。

Selected from:
Y is O or S;
R is straight or branched alkyl, such as methyl, ethyl, propyl, n-butyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, or a C _12-19 long chain alkyl; cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or benzyl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｒ^５は、ＨまたはＤであり；
Ｅは、ＣＨ_２またはＣＤ_２であり；
Ｕは、ＯまたはＳであり；
Ｙは、ＯまたはＳであり；
各Ｘは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
Ｒ^１は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^８、ＳＲ^８、ＮＨＲ^８、ＮＨＯＨ、ＮＲ^８ＯＨ、ＮＨＯＲ^８またはＮＲ^８ＯＲ^８であり；
ここで、式ＩＩＩｂおよびＩＩＩｃにおいて、ＸがＳであるもしくはＲ^１がＳＲ^８である一方、またはＸがＳであるおよびＲ^１がＳＲ^８である両方であり；
ここで、式ＩＩＩｄにおいて、少なくとも１つのＸはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^８であり；
Ｚは、ＣＨ、ＮまたはＣＲ^８であり；
ここで、Ｒ^６、Ｒ^７およびＲ^１０は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^９で置換されてもよいＣ_１－２２アルキルから選択され；
Ｒ^８は、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^９で置換されてもよいＣ_１－２２アルキルであり；
各Ｒ^９は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
Ｒ^５０は、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、分岐アルキルまたはシクロアルキルである。

or a pharma- ceutical acceptable salt thereof, wherein
^R5 is H or D;
E is _CH2 or _CD2 ;
U is O or S;
Y is O or S;
Each X is independently O, S, NH, ^NR8 , NHOH, ^NR8OH , ^{NHOR8 , or NR8OR8 ;
R1} is OH, SH, _NH2 , ^OR8 , ^SR8 , ^NHR8 , NHOH, ^NR8OH , ^{NHOR8 or NR8OR8 ;}
wherein in formula IIIb and IIIc, X is S or R ¹ is SR ⁸ , or both X is S and R ¹ is SR ⁸ ;
wherein in formula IIId, at least one X is S;
W is CH, N or ^CR8 ;
Z is CH, N or ^CR8 ;
wherein R ⁶ , R ⁷ and R ¹⁰ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ⁹ ;
R ⁸ is methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more identical or different R ⁹ ;
Each ^R9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
R ⁵⁰ is a C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, branched alkyl or cycloalkyl.

In certain embodiments, U is S and W and Z are CH. In other embodiments, U is O and W and Z are CH.

In certain embodiments, ^R5 is H. In other embodiments, ^R6 is methyl. In yet other embodiments, ^R7 is hydroxyl. In preferred embodiments, ^R5 is H, ^R6 is methyl, and ^R7 is hydroxyl.

In certain embodiments, R ⁵⁰ is alkyl, methyl, ethyl, propyl, n-butyl, branched alkyl, isopropyl, 2-butyl, 1-ethylpropyl, 1-propylbutyl, cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, or 2-butyl.

In an exemplary embodiment, the compound is

から選択される。

is selected from.

In a particular embodiment, the present invention provides a compound of the formula:

の化合物またはこれらの医薬として許容される塩に関し、式中、
Ｘは、Ｏ、ＣＨ_２またはＣＤ_２であり；
Ｒ^１は、ホスフェート置換基、ホスホネート置換基、ポリホスフェート置換基、ポリホスホネート置換基であり、ここで、ホスフェートまたはポリホスフェートもしくはポリホスホネートにおけるホスフェートは、場合によって、ホスホロボレート、ホスホロチオエートまたはホスホロアミデートであり、該置換基は、１つ以上の同一であるまたは異なるＲ^６で置換されてもよいアミノ酸エステルまたは脂質もしくは誘導体でさらに置換されており；
Ｑは、少なくとも１つのチオン、チオールまたはチオエーテルで置換されている２個以上の窒素ヘテロ原子を含むヘテロシクリルであり、ここでＱは、１つ以上の同一であるまたは異なるアルキル、ハロゲンまたはシクロアルキルで置換されてもよく；
Ｒ^６は、同一であるまたは異なるアルキル、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリールまたはヘテロシクリルであり、ここで各Ｒ^６は、１つ以上の同一であるまたは異なるＲ^７で置換されてもよく；
Ｒ^７は、ハロゲン、ニトロ、シアノ、ヒドロキシ、トリフルオロメトキシ、トリフルオロメチル、アミノ、ホルミル、カルボキシ、カルバモイル、メルカプト、スルファモイル、メチル、エチル、メトキシ、エトキシ、アセチル、アセトキシ、メチルアミノ、エチルアミノ、ジメチルアミノ、ジエチルアミノ、Ｎ－メチル－Ｎ－エチルアミノ、アセチルアミノ、Ｎ－メチルカルバモイル、Ｎ－エチルカルバモイル、Ｎ，Ｎ－ジメチルカルバモイル、Ｎ，Ｎ－ジエチルカルバモイル、Ｎ－メチル－Ｎ－エチルカルバモイル、メチルチオ、エチルチオ、メチルスルフィニル、エチルスルフィニル、メシル、エチルスルホニル、メトキシカルボニル、エトキシカルボニル、Ｎ－メチルスルファモイル、Ｎ－エチルスルファモイル、Ｎ，Ｎ－ジメチルスルファモイル、Ｎ，Ｎ－ジエチルスルファモイル、Ｎ－メチル－Ｎ－エチルスルファモイル、カルボシクリル、アリール、またはヘテロシクリルである。

or a pharma- ceutical acceptable salt thereof, wherein
X is O, _CH2 or _CD2 ;
R ¹ is a phosphate, phosphonate, polyphosphate, or polyphosphonate substituent, where the phosphate or phosphate in the polyphosphate or polyphosphonate is optionally a phosphoroborate, phosphorothioate, or phosphoroamidate, which is further substituted with one or more identical or different R ⁶ amino acid esters or lipids or derivatives;
Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl;
R ⁶ is the same or different alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) ₂ amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl or heterocyclyl, where each R ⁶ may be substituted with one or more of the same or different R ⁷ ;
^R7 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, Q heterocyclyl is pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

In a preferred embodiment, U is O and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine. In another preferred embodiment, U is S and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine.

In certain embodiments, the lipid is a sphingolipid of any of the formulas described above or herein.

In a particular embodiment, the present invention provides a compound of the formula

の化合物またはこの医薬として許容される塩に関し、式中、
各Ｙは、独立して、ＯまたはＳであり；
Ｒ^２３は、ＯまたはＮＨであり；
Ｒ^４およびＲ^７は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^９で置換されてもよいＣ_１－２２アルキルから選択され；
Ｑは、少なくとも１つのチオン、チオールまたはチオエーテルで置換されている２個以上の窒素ヘテロ原子を含むヘテロシクリルであり、ここでＱは、１つ以上の同一であるまたは異なるアルキル、ハロゲンまたはシクロアルキルで置換されてもよく；
各Ｒ^９は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
Ｒ^２０は、１つ以上の同一であるまたは異なるＲ^２６で置換されてもよい６個から２２個の炭素のアルキルであり；
Ｒ^２１およびＲ^２２は、各々独立して、水素、アルキルまたはアルカノイルから選択され、ここでＲ^２１およびＲ^２２は、各々、１つ以上の同一であるまたは異なるＲ^２６で置換されてもよく；
Ｒ^２４およびＲ^２５は、各々独立して、水素、アルキルまたはアリールから選択され、ここでＲ^２４およびＲ^２５は、各々、１つ以上の同一であるまたは異なるＲ^２６で置換されてもよく；
各Ｒ^２６は、独立して、アルキル、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択される。

or a pharma- ceutical acceptable salt thereof, wherein
Each Y is independently O or S;
^R23 is O or NH;
R ⁴ and R ⁷ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ⁹ ;
Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl;
Each ^R9 is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
R ²⁰ is an alkyl of 6 to 22 carbons, optionally substituted with one or more identical or different R ²⁶ ;
R ²¹ and R ²² are each independently selected from hydrogen, alkyl, or alkanoyl, where R ²¹ and R ²² are each optionally substituted with one or more identical or different R ²⁶ ;
R ²⁴ and R ²⁵ are each independently selected from hydrogen, alkyl, or aryl, where R ²⁴ and R ²⁵ are each optionally substituted with one or more identical or different R ²⁶ ;
Each ^R26 is independently selected from alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, R ⁴ and R ⁷ are independently hydrogen, hydroxy, alkoxy, azide, or halogen.

In a particular embodiment, the present invention provides a compound of the formula

の化合物またはこれらの医薬として許容される塩に関し、式中、
点線は、単結合または二重結合の存在を表し；
Ｑは、少なくとも１つのチオン、チオールまたはチオエーテルで置換されている２個以上の窒素ヘテロ原子を含むヘテロシクリルであり、ここでＱは、１つ以上の同一であるまたは異なるアルキル、ハロゲン、シクロアルキルで置換されてもよく；
Ｒ^２３は、ＯまたはＮＨであり；
Ｒ^４およびＲ^７は、各々独立して、Ｈ、Ｄ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニル、アリル、エチニル、ビニル、Ｃ_１－２２アルコキシ、ＯＨ、ＳＨ、ＮＨ_２、Ｎ_３、ＣＨＯ、ＣＮ、Ｃｌ、Ｂｒ、Ｆ、Ｉ、または１つ以上の同一であるもしくは異なるＲ^２６で置換されてもよいＣ_１－２２アルキルから選択され；
Ｒ^２０は、１つ以上の同一であるまたは異なるＲ^２６で置換されてもよい６個から２２個の炭素のアルキルであり；
Ｒ^２１、Ｒ^２２およびＲ^２５は、独立して、水素、アルキルまたはアルカノイルから選択され、ここでＲ^２１、Ｒ^２２およびＲ^２５は、各々、１つ以上の同一であるまたは異なるＲ^２６で置換されてもよく；
各Ｒ^２４は、独立して、水素、アルキルまたはアリールから選択され、ここで各Ｒ^２４は、１つ以上の同一であるまたは異なるＲ^２６で置換されてもよく；
各Ｒ^２６は、独立して、アルキル、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択される。

or a pharma- ceutical acceptable salt thereof, wherein
The dotted lines represent the presence of a single or double bond;
Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl;
^R23 is O or NH;
R ⁴ and R ⁷ are each independently selected from H, D, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl, allyl, ethynyl, vinyl, C _1-22 alkoxy, OH, SH, NH ₂ , N ₃ , CHO, CN, Cl, Br, F, I, or C _1-22 alkyl optionally substituted with one or more identical or different R ²⁶ ;
R ²⁰ is an alkyl of 6 to 22 carbons, optionally substituted with one or more identical or different R ²⁶ ;
R ²¹ , R ²² and R ²⁵ are independently selected from hydrogen, alkyl or alkanoyl, where R ²¹ , R ²² and R ²⁵ are each optionally substituted with one or more identical or different R ²⁶ ;
each R ²⁴ is independently selected from hydrogen, alkyl, or aryl, where each R ²⁴ may be substituted with one or more identical or different R ²⁶ ;
Each ^R26 is independently selected from alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, Q heterocyclyl is pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

In a particular embodiment, the present invention provides a compound of the formula:

を有する化合物またはこの医薬として許容される塩に関し、式中、
Ｘは、ＯまたはＮＨまたはＣＤ_２であり；
Ｙは、ＯまたはＳであり；
Ｒ^２３は、ＯまたはＮＨであり；
Ｑは、少なくとも１つのチオン、チオールまたはチオエーテルで置換されている２個以上の窒素ヘテロ原子を含むヘテロシクリルであり、ここでＱは、１つ以上の同一であるまたは異なるアルキル、ハロゲンまたはシクロアルキルで置換されてもよく；
Ｒ^２０は、１つ以上の同一であるまたは異なるＲ^３７で置換されてもよい６個から２２個の炭素のアルキルであり；
Ｒ^２１およびＲ^２２は、各々独立して、水素、アルキルまたはアルカノイルから選択され、ここでＲ^２１およびＲ^２２は、各々、１つ以上の同一であるまたは異なるＲ^３７で置換されてもよく；
Ｒ^２４は、水素、アルキルまたはアリールであり、ここでＲ^２４は、１つ以上の同一であるまたは異なるＲ^３７で置換されてもよく；
Ｒ^２６は、アルキルであり；
各Ｒ^３７は、独立して、アルキル、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択される。

or a pharma- ceutical acceptable salt thereof, wherein
X is O or NH or _CD2 ;
Y is O or S;
^R23 is O or NH;
Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl;
R ²⁰ is an alkyl of 6 to 22 carbons, optionally substituted with one or more of the same or different R ³⁷ ;
R ²¹ and R ²² are each independently selected from hydrogen, alkyl, or alkanoyl, where R ²¹ and R ²² are each optionally substituted with one or more of the same or different R ³⁷ ;
R ²⁴ is hydrogen, alkyl or aryl, where R ²⁴ may be substituted with one or more identical or different R ³⁷ ;
R ²⁶ is alkyl;
Each R ³⁷ is independently selected from alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) ₂ amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, Q heterocyclyl is pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

In a particular embodiment, the present invention provides a compound of the formula:

を有する化合物またはこれらの医薬として許容される塩に関し、式中、
Ｘは、ＯまたはＮＨまたはＣＤ_２であり；
Ｙは、ＯまたはＳであり；
Ｒ^２３は、ＯまたはＮＨであり；
Ｑは、少なくとも１つのチオン、チオールまたはチオエーテルで置換されている２個以上の窒素ヘテロ原子を含むヘテロシクリルであり、ここでＱは、１つ以上の同一であるまたは異なるアルキル、ハロゲンまたはシクロアルキルで置換されてもよく；
Ｒ^２７は、１つ以上の同一であるまたは異なるＲ^３７で置換されてもよい６個から２２個の炭素のアルキルであり；
Ｒ^２１、Ｒ^２２、Ｒ^２８およびＲ^２９は、各々独立して、水素、アルキルまたはアルカノイルから選択され、ここでＲ^２１、Ｒ^２２、Ｒ^２８およびＲ^２９は、各々、１つ以上の同一であるまたは異なるＲ^３７で置換されてもよく；
Ｒ^２４は、水素、アルキルまたはアリールであり、ここでＲ^２４は、１つ以上の同一であるまたは異なるＲ^３７で置換されてもよく；
Ｒ^２６は、アルキルであり；
各Ｒ^３７は、独立して、アルキル、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択される。

or a pharma- ceutical acceptable salt thereof, wherein
X is O or NH or _CD2 ;
Y is O or S;
^R23 is O or NH;
Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where Q is optionally substituted with one or more of the same or different alkyl, halogen, or cycloalkyl;
R ²⁷ is an alkyl of 6 to 22 carbons, optionally substituted with one or more of the same or different R ³⁷ ;
R ²¹ , R ²² , R ²⁸ and R ²⁹ are each independently selected from hydrogen, alkyl or alkanoyl, where R ²¹ , R ²² , R ²⁸ and R ²⁹ are each optionally substituted with one or more identical or different R ³⁷ ;
R ²⁴ is hydrogen, alkyl or aryl, where R ²⁴ may be substituted with one or more identical or different R ³⁷ ;
R ²⁶ is alkyl;
Each R ³⁷ is independently selected from alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) ₂ amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl.

In certain embodiments, Q heterocyclyl is pyrimidine-2-one-4-thione, pyrimidine-2-thione-4-one, pyrimidine-2,4-dithione, 4-aminopyrimidine-2-thione, 5-fluoropyrimidine-2-one-4-thione, 5-fluoropyrimidine-2-thione-4-one, 5-fluoropyrimidine-2,4-dithione, 4-amino-5-fluoropyrimidine-2-thione, 2-amino-purine-6-thione, 2-amino-7-deaza-purine-6-thione, or 2-amino-7-deaza-7-substituted purine-6-thione.

In a preferred embodiment, U is O and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine. In another preferred embodiment, U is S and Q is said pyrimidine having at least one thione, thiol or thioether at the 2- and/or 4-position of the pyrimidine.

In certain embodiments, the fragment defined by R ²³ -R ²⁷ is a sphingolipid. Suitable sphingolipids include, but are not limited to, 2-aminooctadecane-3,5-diol; (2S,3S,5S)-2-aminooctadecane-3,5-diol; (2S,3R,5S)-2-aminooctadecane-3,5-diol; 2-(methylamino)octadecane-3,5-diol; (2S,3R,5S)-2-(methylamino)octadecane-3,5-diol; 2-(dimethylamino)octadecane-3,5-diol; (2R,3S,5S)-2-(dimethylamino)octadecane-3,5-diol; 1-(pyrrolidin-2-yl)hexadecane-1,3-diol; (1S,3S)-1-((S) -pyrrolidin-2-yl)hexadecane-1,3-diol; 2-amino-11,11-difluorooctadecane-3,5-diol; (2S,3S,5S)-2-amino-11,11-difluorooctadecane-3,5-diol; 11,11-difluoro-2-(methylamino)octadecane-3,5-diol; (2S,3S,5S)-11,11-difluoro-2-(methylamino)octadecane-3,5-diol; N-((2S,3S,5S)-3,5-dihydroxyoctadecane-2-yl)acetamide; N-((2S,3S,5S)-3,5-dihydroxyoctadecane-2-yl)palmitamide; 1-( 1-aminocyclopropyl)hexadecane-1,3-diol; (1S,3R)-1-(1-aminocyclopropyl)hexadecane-1,3-diol; (1S,3S)-1-(1-aminocyclopropyl)hexadecane-1,3-diol; 2-amino-2-methyloctadecane-3,5-diol; (3S,5S)-2-amino-2-methyloctadecane-3,5-diol; (3S,5R)-2-amino-2-methyloctadecane-3,5-diol; (3S,5S)-2-methyl-2-(methylamino)octadecane-3,5-diol; 2-amino-5-hydroxy-2-methyloctadecane-3-one; (Z)- These include 2-amino-5-hydroxy-2-methyloctadecane-3-one oxime; (2S,3R,5R)-2-amino-6,6-difluorooctadecane-3,5-diol; (2S,3S,5R)-2-amino-6,6-difluorooctadecane-3,5-diol; (2S,3S,5S)-2-amino-6,6-difluorooctadecane-3,5-diol; (2S,3R,5S)-2-amino-6,6-difluorooctadecane-3,5-diol; and (2S,3S,5S)-2-amino-18,18,18-trifluorooctadecane-3,5-diol; which may be substituted with one or more substituents.

In a preferred embodiment, the nucleoside conjugate or a pharma- cically acceptable salt thereof has the following structure:

を有し、式中、
Ｒ_１は、Ｈ、モノホスフェート、ジホスフェート、トリホスフェートであり、または以下：

wherein
_R1 is H, monophosphate, diphosphate, triphosphate, or the following:

の１つから選択され；
Ｒ_２は、アルキル、分岐アルキルまたはシクロアルキルであり；
Ｒ_３は、アリール、ビアリールまたは置換アリールである。

is selected from one of:
_R2 is alkyl, branched alkyl or cycloalkyl;
_R3 is aryl, biaryl or substituted aryl.

In an exemplary embodiment, the nucleoside conjugated to the phosphorus moiety or a pharma- ceutically acceptable salt thereof has the following structure:

を有する。

has.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ａは、存在しない、またはＣＨ_２、ＣＤ_２、Ｏ、ＣＨ_２Ｏ、ＣＤ_２Ｏ、ＯＣＨ_２もしくはＯＣＤ_２から選択され；
Ｒ_１は、以下：

or a pharma- ceutical acceptable salt thereof, wherein
A is absent or selected from _CH2 , _CD2 , O, _CH2O , _CD2O , _OCH2 , or _OCD2 ;
_R1 is the following:

の１つから選択され、
Ｘは、Ｏ、Ｓ、ＮＨ、ＣＨ_２、ＣＤ_２、ＣＨＦ、ＣＦ_２、ＣＣＨ_２またはＣＣＦ_２であり；
各Ｕは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
各Ｒ^８は、独立して、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^９、ＳＲ^９、ＮＨＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
ここで、式ＸａおよびＸｂにおいて、ＵがＳであるもしくはＲ^８がＳＲ^９である一方、またはＵがＳであるおよびＲ^８がＳＲ^９である両方であり；
ここで、式Ｘｃにおいて、少なくとも１つのＵはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^９であり；
Ｚは、ＣＨ、ＮまたはＣＲ^９であり；
各Ｒ^９は、独立して、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニルアリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
各Ｒ_２は、独立して、水素、重水素、ヒドロキシル、シアノ、ハロゲン、フルオロ、メチル、エチニル、ビニル、アリル、モノフルオロメチル、ジフルオロメチル、トリフルオロメチル、トリデューテロメチル、アジド、メトキシまたはアミノから選択され；
各Ｒ_３は、独立して、水素、重水素、ヒドロキシル、シアノ、ハロゲン、フルオロ、メチル、エチニル、ビニル、アリル、モノフルオロメチル、ジフルオロメチル、トリフルオロメチル、トリデューテロメチルまたはアジドから選択され；
各Ｒ_４は、独立して、水素、重水素、ヒドロキシル、ハロゲン、フルオロ、アジド、メトキシまたはアミノから選択され；
脂質は、本明細書に記載されている通りであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ_５は、アルキル、分岐アルキルまたはシクロアルキルであり；
アリールは、本明細書に記載されている通りであり；
Ｒ_６は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_７は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

is selected from one of
X is O, S, NH, _CH2 , _CD2 , CHF, _CF2 , _CCH2 or _CCF2 ;
each U is independently O, S, NH, ^NR9 , NHOH, ^NR9OH , ^{NHOR9 , or NR9OR9 ;}
each ^R8 is independently OH, SH, _NH2 , OR9, ^SR9 , ^NHR9 , ^NHOH , ^NR9OH , ^{NHOR9 ,} or ^NR9OR9 ;
wherein in formulae Xa and Xb, U is S or R ⁸ is SR ⁹ , or both U is S and R ⁸ is SR ⁹ ;
wherein in formula Xc, at least one U is S;
W is CH, N or ^CR9 ;
Z is CH, N or ^CR9 ;
each R ⁹ is independently methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinylallyl, halogen, alkyl halide, hydroxylalkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more of the same or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
Each _R2 is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, azido, methoxy, or amino;
Each _R3 is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, or azido;
Each _R4 is independently selected from hydrogen, deuterium, hydroxyl, halogen, fluoro, azido, methoxy, or amino;
The lipid is as described herein;
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
_R5 is alkyl, branched alkyl or cycloalkyl;
Aryl is as described herein;
R ₆ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
R ₇ is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ａは、存在しない、またはＣＨ_２、ＣＤ_２、Ｏ、ＣＨ_２Ｏ、ＣＤ_２Ｏ、ＯＣＨ_２もしくはＯＣＤ_２から選択され；
Ｒ_１は、以下：

or a pharma- ceutical acceptable salt thereof, wherein
A is absent or selected from _CH2 , _CD2 , O, _CH2O , _CD2O , _OCH2 , or _OCD2 ;
_R1 is the following:

の１つから選択され、
Ｘは、Ｏ、Ｓ、ＮＨ、ＣＨ_２、ＣＤ_２、ＣＨＦ、ＣＦ_２、ＣＣＨ_２またはＣＣＦ_２であり；
各Ｒ_２は、独立して、水素、重水素、ヒドロキシル、シアノ、ハロゲン、フルオロ、メチル、エチニル、ビニル、アリル、モノフルオロメチル、ジフルオロメチル、トリフルオロメチル、トリデューテロメチル、アジド、メトキシまたはアミノであり；
各Ｒ_３は、独立して、水素、重水素、ヒドロキシル、シアノ、ハロゲン、フルオロ、メチル、エチニル、ビニル、アリル、モノフルオロメチル、ジフルオロメチル、トリフルオロメチル、トリデューテロメチルまたはアジドであり；
各Ｒ_４は、独立して、水素、重水素、ヒドロキシル、ハロゲン、フルオロ、アジド、メトキシまたはアミノであり；
脂質は、本明細書に記載されている通りであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ_５は、アルキル、分岐アルキルまたはシクロアルキルであり；
アリールは、本明細書に記載されている通りであり；
Ｒ_６は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_７は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

is selected from one of
X is O, S, NH, _CH2 , _CD2 , CHF, _CF2 , _CCH2 or _CCF2 ;
Each _R2 is independently hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, azido, methoxy, or amino;
each _R3 is independently hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, or azido;
Each _R4 is independently hydrogen, deuterium, hydroxyl, halogen, fluoro, azido, methoxy, or amino;
The lipid is as described herein;
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
_R5 is alkyl, branched alkyl or cycloalkyl;
Aryl is as described herein;
R ₆ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
R ₇ is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ａは、存在しない、またはＣＨ_２、ＣＤ_２、Ｏ、ＣＨ_２Ｏ、ＣＤ_２Ｏ、ＯＣＨ_２もしくはＯＣＤ_２から選択され；
Ｒ_１は、以下：

or a pharma- ceutical acceptable salt thereof, wherein
A is absent or selected from _CH2 , _CD2 , O, _CH2O , _CD2O , _OCH2 , or _OCD2 ;
_R1 is the following:

の１つから選択され、
Ｘは、Ｏ、Ｓ、ＮＨ、ＣＨ_２、ＣＤ_２、ＣＨＦ、ＣＦ_２、ＣＣＨ_２またはＣＣＦ_２であり；
各Ｒ_２は、独立して、水素、重水素、ヒドロキシル、シアノ、ハロゲン、フルオロ、メチル、エチニル、ビニル、アリル、モノフルオロメチル、ジフルオロメチル、トリフルオロメチル、トリデューテロメチル、アジド、メトキシまたはアミノであり；
各Ｒ_３は、独立して、水素、重水素、ヒドロキシル、シアノ、ハロゲン、フルオロ、メチル、エチニル、ビニル、アリル、モノフルオロメチル、ジフルオロメチル、トリフルオロメチル、トリデューテロメチルまたはアジドであり；
各Ｒ_４は、独立して、水素、重水素、ヒドロキシル、ハロゲン、フルオロ、アジド、メトキシまたはアミノであり；
脂質は、本明細書に記載されている通りであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ_５は、アルキル、分岐アルキルまたはシクロアルキルであり；
アリールは、本明細書に記載されている通りであり；
Ｒ_６は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_７は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

is selected from one of
X is O, S, NH, _CH2 , _CD2 , CHF, _CF2 , _CCH2 or _CCF2 ;
Each _R2 is independently hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, azido, methoxy, or amino;
Each _R3 is independently hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, or azido;
Each _R4 is independently hydrogen, deuterium, hydroxyl, halogen, fluoro, azido, methoxy, or amino;
The lipid is as described herein;
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
_R5 is alkyl, branched alkyl or cycloalkyl;
Aryl is as described herein;
R ₆ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
R ₇ is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ａは、存在しない、またはＣＨ_２、ＣＤ_２、Ｏ、ＣＨ_２Ｏ、ＣＤ_２Ｏ、ＯＣＨ_２もしくはＯＣＤ_２から選択され；
Ｘは、Ｏ、Ｓ、ＮＨ、ＣＨ_２、ＣＤ_２、ＣＨＦ、ＣＦ_２、ＣＣＨ_２またはＣＣＦ_２であり；
Ｑは、少なくとも１つのチオン、チオールまたはチオエーテルで置換されている２個以上の窒素ヘテロ原子を含むヘテロシクリルであり、ここでＱは、１つ以上の同一であるまたは異なるアルキル、ハロゲン、シクロアルキルで置換されてもよく；
各Ｒ_２は、独立して、水素、重水素、ヒドロキシル、シアノ、ハロゲン、フルオロ、メチル、エチニル、ビニル、アリル、モノフルオロメチル、ジフルオロメチル、トリフルオロメチル、トリデューテロメチル、アジド、メトキシまたはアミノであり；
各Ｒ_３は、独立して、水素、重水素、ヒドロキシル、シアノ、ハロゲン、フルオロ、メチル、エチニル、ビニル、アリル、モノフルオロメチル、ジフルオロメチル、トリフルオロメチル、トリデューテロメチルまたはアジドであり；
各Ｒ_４は、独立して、水素、重水素、ヒドロキシル、ハロゲン、フルオロ、アジド、メトキシまたはアミノであり；
Ｙは、ＯまたはＳであり；
Ｒ_５は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

or a pharma- ceutical acceptable salt thereof, wherein
A is absent or selected from _CH2 , _CD2 , O, _CH2O , _CD2O , _OCH2 , or _OCD2 ;
X is O, S, NH, _CH2 , _CD2 , CHF, _CF2 , _CCH2 or _CCF2 ;
Q is a heterocyclyl containing two or more nitrogen heteroatoms substituted with at least one thione, thiol, or thioether, where Q is optionally substituted with one or more of the same or different alkyl, halogen, cycloalkyl;
Each _R2 is independently hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, azido, methoxy, or amino;
Each _R3 is independently hydrogen, deuterium, hydroxyl, cyano, halogen, fluoro, methyl, ethynyl, vinyl, allyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trideuteromethyl, or azido;
Each _R4 is independently hydrogen, deuterium, hydroxyl, halogen, fluoro, azido, methoxy, or amino;
Y is O or S;
_R5 is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ａは、存在しない、またはＣＨ_２、ＣＤ_２、Ｏ、ＣＨ_２Ｏ、ＣＤ_２Ｏ、ＯＣＨ_２もしくはＯＣＤ_２から選択され；
Ｒ_１は、以下：

or a pharma- ceutical acceptable salt thereof, wherein
A is absent or selected from _CH2 , _CD2 , O, _CH2O , _CD2O , _OCH2 , or _OCD2 ;
_R1 is the following:

の１つから選択され、
Ｘは、Ｏ、Ｓ、ＮＨ、ＣＨ_２、ＣＤ_２、ＣＨＦ、ＣＦ_２、ＣＣＨ_２またはＣＣＦ_２であり；
各Ｕは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
Ｒ^８は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^９、ＳＲ^９、ＮＨＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
ここで、式ＸＩＩＩａおよびＸＩＩＩｂにおいて、ＵがＳであるもしくはＲ^８がＳＲ^９である一方、またはＵがＳであるおよびＲ^８がＳＲ^９である両方であり；
ここで、式ＸＩＩＩｃにおいて、少なくとも１つのＵはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^９であり；
Ｚは、ＣＨ、ＮまたはＣＲ^９であり；
各Ｒ^９は、独立して、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
脂質は、本明細書に記載されている通りであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ_５は、アルキル、分岐アルキルまたはシクロアルキルであり；
アリールは、本明細書に記載されている通りであり；
Ｒ_６は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_７は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

is selected from one of
X is O, S, NH, _CH2 , _CD2 , CHF, _CF2 , _CCH2 or _CCF2 ;
each U is independently O, S, NH, ^NR9 , NHOH, ^NR9OH , ^{NHOR9 , or NR9OR9 ;
R8} is OH, SH, _NH2 , ^OR9 , ^SR9 , ^NHR9 , NHOH, ^NR9OH , ^{NHOR9 or NR9OR9 ;}
wherein in formulae XIIIa and XIIIb, U is S or R ⁸ is SR ⁹ , or U is S and R ⁸ is SR ⁹ ;
wherein in formula XIIIc, at least one U is S;
W is CH, N or ^CR9 ;
Z is CH, N or ^CR9 ;
each R ⁹ is independently methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more of the same or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
The lipid is as described herein;
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
_R5 is alkyl, branched alkyl or cycloalkyl;
Aryl is as described herein;
R ₆ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
R ₇ is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｒ_１は、以下：

or a pharma- ceutical acceptable salt thereof, wherein
_R1 is the following:

の１つから選択され、
各Ｕは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
Ｒ^８は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^９、ＳＲ^９、ＮＨＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
ここで、式ＸＩＶａおよびＸＩＶｂにおいて、ＵがＳであるもしくはＲ^８がＳＲ^９である一方、またはＵがＳであるおよびＲ^８がＳＲ^９である両方であり；
ここで、式ＸＩＶｃにおいて、少なくとも１つのＵはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^９であり；
Ｚは、ＣＨ、ＮまたはＣＲ^９であり；
各Ｒ^９は、独立して、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
脂質は、本明細書に記載されている通りであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ_５は、アルキル、分岐アルキルまたはシクロアルキルであり；
アリールは、本明細書に記載されている通りであり；
Ｒ_６は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_７は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

is selected from one of
each U is independently O, S, NH, ^NR9 , NHOH, ^NR9OH , ^{NHOR9 , or NR9OR9 ;
R8} is OH, SH, _NH2 , ^OR9 , ^SR9 , ^NHR9 , NHOH, ^NR9OH , ^{NHOR9 or NR9OR9 ;}
wherein in formulae XIVa and XIVb, U is S or R ⁸ is SR ⁹ , or both U is S and R ⁸ is SR ⁹ ;
wherein in formula XIVc, at least one U is S;
W is CH, N or ^CR9 ;
Z is CH, N or ^CR9 ;
each R ⁹ is independently methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more of the same or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
The lipid is as described herein;
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
_R5 is alkyl, branched alkyl or cycloalkyl;
Aryl is as described herein;
R ₆ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
R ₇ is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ａは、存在しない、またはＣＨ_２、ＣＤ_２、Ｏ、ＣＨ_２Ｏ、ＣＤ_２Ｏ、ＯＣＨ_２もしくはＯＣＤ_２から選択され；
Ｒ_１は、以下：

or a pharma- ceutical acceptable salt thereof, wherein
A is absent or selected from _CH2 , _CD2 , O, _CH2O , _CD2O , _OCH2 , or _OCD2 ;
_R1 is the following:

の１つから選択され、
Ｘは、Ｏ、Ｓ、ＮＨ、ＣＨ_２、ＣＤ_２、ＣＨＦ、ＣＦ_２、ＣＣＨ_２またはＣＣＦ_２であり；
各Ｕは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９、またはＮＲ^９ＯＲ^９であり；
Ｒ^８は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^９、ＳＲ^９、ＮＨＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
ここで、式ＸＶａおよびＸＶｂにおいて、ＵがＳであるもしくはＲ^８がＳＲ^９である一方、またはＵがＳであるおよびＲ^８がＳＲ^９である両方であり；
ここで、式ＸＶｃにおいて、少なくとも１つのＵはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^９であり；
Ｚは、ＣＨ、ＮまたはＣＲ^９であり；
各Ｒ^９は、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリールまたはヘテロシクリルから選択され；
脂質は、本明細書に記載されている通りであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ_５は、アルキル、分岐アルキルまたはシクロアルキルであり；
アリールは、本明細書に記載されている通りであり；
Ｒ_６は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_７は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

is selected from one of
X is O, S, NH, _CH2 , _CD2 , CHF, _CF2 , _CCH2 or _CCF2 ;
each U is independently O, S, NH, NR ⁹ , NHOH, NR ⁹ OH, NHOR ⁹ , or NR ⁹ OR ⁹ ;
^R8 is OH, SH, _NH2 , ^OR9 , ^SR9 , ^NHR9 , NHOH, ^NR9OH , ^{NHOR9 or NR9OR9 ;}
wherein in formulae XVa and XVb, U is S or R ⁸ is SR ⁹ , or U is S and R ⁸ is SR ⁹ ;
wherein in formula XVc, at least one U is S;
W is CH, N or ^CR9 ;
Z is CH, N or ^CR9 ;
each R ⁹ is methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more identical or different R ¹⁰ ;
Each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
The lipid is as described herein;
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
_R5 is alkyl, branched alkyl or cycloalkyl;
Aryl is as described herein;
R ₆ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
R ₇ is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｒ_１は、以下：

or a pharma- ceutical acceptable salt thereof, wherein
_R1 is the following:

の１つから選択され、
各Ｕは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
Ｒ^８は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^９、ＳＲ^９、ＮＨＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
ここで、式ＸＶＩａおよびＸＶＩｂにおいて、ＵがＳであるもしくはＲ^８がＳＲ^９である一方、またはＵがＳであるおよびＲ^８がＳＲ^９である両方であり；
ここで、式ＸＶＩｃにおいて、少なくとも１つのＵはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^９であり；
Ｚは、ＣＨ、ＮまたはＣＲ^９であり；
各Ｒ^９は、独立して、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
脂質は、本明細書に記載されている通りであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ_５は、アルキル、分岐アルキルまたはシクロアルキルであり；
アリールは、本明細書に記載されている通りであり；
Ｒ_６は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_７は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

is selected from one of
each U is independently O, S, NH, ^NR9 , NHOH, ^NR9OH , ^{NHOR9 , or NR9OR9 ;
R8} is OH, SH, _NH2 , ^OR9 , ^SR9 , ^NHR9 , NHOH, ^NR9OH , ^{NHOR9 or NR9OR9 ;}
wherein in formula XVIa and XVIb, U is S or R ⁸ is SR ⁹ , or both U is S and R ⁸ is SR ⁹ ;
wherein in formula XVIc, at least one U is S;
W is CH, N or ^CR9 ;
Z is CH, N or ^CR9 ;
each R ⁹ is independently methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more of the same or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
The lipid is as described herein;
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
_R5 is alkyl, branched alkyl or cycloalkyl;
Aryl is as described herein;
R ₆ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
R ₇ is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｒ_１は、以下：

or a pharma- ceutical acceptable salt thereof, wherein
_R1 is the following:

の１つから選択され、
各Ｕは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
Ｒ^８は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^９、ＳＲ^９、ＮＨＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
ここで、式ＸＶＩＩａおよびＸＶＩＩｂにおいて、ＵがＳであるもしくはＲ^８がＳＲ^９である一方、またはＵがＳであるおよびＲ^８がＳＲ^９である両方であり；
ここで、式ＸＶＩＩｃにおいて、少なくとも１つのＵはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^９であり；
Ｚは、ＣＨ、ＮまたはＣＲ^９であり；
各Ｒ^９は、独立して、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
脂質は、本明細書に記載されている通りであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ_５は、アルキル、分岐アルキルまたはシクロアルキルであり；
アリールは、本明細書に記載されている通りであり；
Ｒ_６は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_７は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

is selected from one of
each U is independently O, S, NH, ^NR9 , NHOH, ^NR9OH , ^{NHOR9 , or NR9OR9 ;
R8} is OH, SH, _NH2 , ^OR9 , ^SR9 , ^NHR9 , NHOH, ^NR9OH , ^{NHOR9 or NR9OR9 ;}
wherein in formula XVIIa and XVIIb, U is S or R ⁸ is SR ⁹ , or U is S and R ⁸ is SR ⁹ ;
wherein in Formula XVIIc, at least one U is S;
W is CH, N or ^CR9 ;
Z is CH, N or ^CR9 ;
each R ⁹ is independently methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more of the same or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
The lipid is as described herein;
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
_R5 is alkyl, branched alkyl or cycloalkyl;
Aryl is as described herein;
R ₆ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
R ₇ is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ａは、存在しない、またはＣＨ_２、ＣＤ_２、Ｏ、ＣＨ_２Ｏ、ＣＤ_２Ｏ、ＯＣＨ_２もしくはＯＣＤ_２から選択され；
Ｒ_１は、以下：

or a pharma- ceutical acceptable salt thereof, wherein
A is absent or selected from _CH2 , _CD2 , O, _CH2O , _CD2O , _OCH2 , or _OCD2 ;
_R1 is the following:

の１つから選択され、
Ｘは、Ｏ、Ｓ、ＮＨ、ＣＨ_２、ＣＤ_２、ＣＨＦ、ＣＦ_２、ＣＣＨ_２またはＣＣＦ_２であり；
各Ｕは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
Ｒ^８は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^９、ＳＲ^９、ＮＨＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
ここで、式ＸＶＩＩＩａおよびＸＶＩＩＩｂにおいて、ＵがＳであるもしくはＲ^８がＳＲ^９である一方、またはＵがＳであるおよびＲ^８がＳＲ^９である両方であり；
ここで、式ＸＶＩＩＩｃにおいて、少なくとも１つのＵはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^９であり；
Ｚは、ＣＨ、ＮまたはＣＲ^９であり；
各Ｒ^９は、独立して、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
脂質は、本明細書に記載されている通りであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ_５は、アルキル、分岐アルキルまたはシクロアルキルであり；
アリールは、本明細書に記載されている通りであり；
Ｒ_６は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_７は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

is selected from one of
X is O, S, NH, _CH2 , _CD2 , CHF, _CF2 , _CCH2 or _CCF2 ;
each U is independently O, S, NH, ^NR9 , NHOH, ^NR9OH , ^{NHOR9 , or NR9OR9 ;
R8} is OH, SH, _NH2 , ^OR9 , ^SR9 , ^NHR9 , NHOH, ^NR9OH , ^{NHOR9 or NR9OR9 ;}
wherein in formulae XVIIIa and XVIIIb, U is S or R ⁸ is SR ⁹ , or U is S and R ⁸ is SR ⁹ ;
wherein in formula XVIIIc, at least one U is S;
W is CH, N or ^CR9 ;
Z is CH, N or ^CR9 ;
each R ⁹ is independently methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more of the same or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
The lipid is as described herein;
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
_R5 is alkyl, branched alkyl or cycloalkyl;
Aryl is as described herein;
R ₆ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
R ₇ is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｒ_１は、以下：

or a pharma- ceutical acceptable salt thereof, wherein
_R1 is the following:

の１つから選択され、
各Ｕは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
Ｒ^８は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^９、ＳＲ^９、ＮＨＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
ここで、式ＸＩＸａおよびＸＩＸｂにおいて、ＵがＳであるもしくはＲ^８がＳＲ^９である一方、またはＵがＳであるおよびＲ^８がＳＲ^９である両方であり；
ここで、式ＸＩＸｃにおいて、少なくとも１つのＵはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^９であり；
Ｚは、ＣＨ、ＮまたはＣＲ^９であり；
Ｒ^９は、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
脂質は、本明細書に記載されている通りであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ_５は、アルキル、分岐アルキルまたはシクロアルキルであり；
アリールは、本明細書に記載されている通りであり；
Ｒ_６は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_７は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

is selected from one of
each U is independently O, S, NH, ^NR9 , NHOH, ^NR9OH , ^{NHOR9 , or NR9OR9 ;
R8} is OH, SH, _NH2 , ^OR9 , ^SR9 , ^NHR9 , NHOH, ^NR9OH , ^{NHOR9 or NR9OR9 ;}
wherein in formulae XIXa and XIXb, U is S or R ⁸ is SR ⁹ , or U is S and R ⁸ is SR ⁹ ;
wherein in formula XIXc, at least one U is S;
W is CH, N or ^CR9 ;
Z is CH, N or ^CR9 ;
R ⁹ is methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more identical or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
The lipid is as described herein;
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
_R5 is alkyl, branched alkyl or cycloalkyl;
Aryl is as described herein;
R ₆ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
R ₇ is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ａは、存在しない、またはＣＨ_２、ＣＤ_２、Ｏ、ＣＨ_２Ｏ、ＣＤ_２Ｏ、ＯＣＨ_２もしくはＯＣＤ_２から選択され；
Ｒ_１は、以下：

or a pharma- ceutical acceptable salt thereof, wherein
A is absent or selected from _CH2 , _CD2 , O, _CH2O , _CD2O , _OCH2 , or _OCD2 ;
_R1 is the following:

の１つから選択され、
Ｘは、Ｏ、Ｓ、ＮＨ、ＣＨ_２、ＣＤ_２、ＣＨＦ、ＣＦ_２、ＣＣＨ_２またはＣＣＦ_２であり；
各Ｕは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
Ｒ^８は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^９、ＳＲ^９、ＮＨＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
ここで、式ＸＸａおよびＸＸｂにおいて、ＵがＳであるもしくはＲ^８がＳＲ^９である一方、またはＵがＳであるおよびＲ^８がＳＲ^９である両方であり；
ここで、式ＸＸｃにおいて、少なくとも１つのＵはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^９であり；
Ｚは、ＣＨ、ＮまたはＣＲ^９であり；
各Ｒ^９は、独立して、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
脂質は、本明細書に記載されている通りであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ_５は、アルキル、分岐アルキルまたはシクロアルキルであり；
アリールは、本明細書に記載されている通りであり；
Ｒ_６は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_７は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

is selected from one of
X is O, S, NH, _CH2 , _CD2 , CHF, _CF2 , _CCH2 or _CCF2 ;
each U is independently O, S, NH, ^NR9 , NHOH, ^NR9OH , ^{NHOR9 , or NR9OR9 ;
R8} is OH, SH, _NH2 , ^OR9 , ^SR9 , ^NHR9 , NHOH, ^NR9OH , ^{NHOR9 or NR9OR9 ;}
wherein in formula XXa and XXb, either U is S or R ⁸ is SR ⁹ , or both U is S and R ⁸ is SR ⁹ ;
wherein in formula XXc, at least one U is S;
W is CH, N or ^CR9 ;
Z is CH, N or ^CR9 ;
each R ⁹ is independently methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more of the same or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
The lipid is as described herein;
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
_R5 is alkyl, branched alkyl or cycloalkyl;
Aryl is as described herein;
R ₆ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
R ₇ is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｒ_１は、以下：

or a pharma- ceutical acceptable salt thereof, wherein
_R1 is the following:

の１つから選択され、
各Ｕは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
Ｒ^８は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^９、ＳＲ^９、ＮＨＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
ここで、式ＸＸＩａおよびＸＸＩｂにおいて、ＵがＳであるもしくはＲ^８がＳＲ^９である一方、またはＵがＳであるおよびＲ^８がＳＲ^９である両方であり；
ここで、式ＸＸＩｃにおいて、少なくとも１つのＵはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^９であり；
Ｚは、ＣＨ、ＮまたはＣＲ^９であり；
各Ｒ^９は、独立して、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
脂質は、本明細書に記載されている通りであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ_５は、アルキル、分岐アルキルまたはシクロアルキルであり；
アリールは、本明細書に記載されている通りであり；
Ｒ_６は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_７は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

is selected from one of
each U is independently O, S, NH, ^NR9 , NHOH, ^NR9OH , ^{NHOR9 , or NR9OR9 ;
R8} is OH, SH, _NH2 , ^OR9 , ^SR9 , ^NHR9 , NHOH, ^NR9OH , ^{NHOR9 or NR9OR9 ;}
wherein in formula XXIa and XXIb, U is S or R ⁸ is SR ⁹ , or U is S and R ⁸ is SR ⁹ ;
wherein in formula XXIc, at least one U is S;
W is CH, N or ^CR9 ;
Z is CH, N or ^CR9 ;
each R ⁹ is independently methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more of the same or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
The lipid is as described herein;
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
_R5 is alkyl, branched alkyl or cycloalkyl;
Aryl is as described herein;
R ₆ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
R ₇ is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ａは、存在しない、またはＣＨ_２、ＣＤ_２、Ｏ、ＣＨ_２Ｏ、ＣＤ_２Ｏ、ＯＣＨ_２もしくはＯＣＤ_２から選択され；
Ｒ_１は、以下：

or a pharma- ceutical acceptable salt thereof, wherein
A is absent or selected from _CH2 , _CD2 , O, _CH2O , _CD2O , _OCH2 , or _OCD2 ;
_R1 is the following:

の１つから選択され、
Ｘは、Ｏ、Ｓ、ＮＨ、ＣＨ_２、ＣＤ_２、ＣＨＦ、ＣＦ_２、ＣＣＨ_２またはＣＣＦ_２であり；
各Ｕは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
Ｒ^８は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^９、ＳＲ^９、ＮＨＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
ここで、式ＸＸＩＩａおよびＸＸＩＩｂにおいて、ＵがＳであるもしくはＲ^８がＳＲ^９である一方、またはＵがＳであるおよびＲ^８がＳＲ^９である両方であり；
ここで、式ＸＸＩＩｃにおいて、少なくとも１つのＵはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^９であり；
Ｚは、ＣＨ、ＮまたはＣＲ^９であり；
各Ｒ^９は、独立して、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
脂質は、本明細書に記載されている通りであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ_５は、アルキル、分岐アルキルまたはシクロアルキルであり；
アリールは、本明細書に記載されている通りであり；
Ｒ_６は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_７は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

is selected from one of
X is O, S, NH, _CH2 , _CD2 , CHF, _CF2 , _CCH2 or _CCF2 ;
each U is independently O, S, NH, ^NR9 , NHOH, ^NR9OH , ^{NHOR9 , or NR9OR9 ;
R8} is OH, SH, _NH2 , ^OR9 , ^SR9 , ^NHR9 , NHOH, ^NR9OH , ^{NHOR9 or NR9OR9 ;}
wherein in formula XXIIa and XXIIb, U is S or R ⁸ is SR ⁹ , or both U is S and R ⁸ is SR ⁹ ;
wherein in formula XXIIc, at least one U is S;
W is CH, N or ^CR9 ;
Z is CH, N or ^CR9 ;
each R ⁹ is independently methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more of the same or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
The lipid is as described herein;
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
_R5 is alkyl, branched alkyl or cycloalkyl;
Aryl is as described herein;
R ₆ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
R ₇ is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

In certain embodiments, the disclosure provides a compound of the formula:

の化合物またはこの医薬として許容される塩に関し、式中、
Ｒ_１は、以下：

or a pharma- ceutical acceptable salt thereof, wherein
_R1 is the following:

の１つから選択され、
各Ｕは、独立して、Ｏ、Ｓ、ＮＨ、ＮＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
Ｒ^８は、ＯＨ、ＳＨ、ＮＨ_２、ＯＲ^９、ＳＲ^９、ＮＨＲ^９、ＮＨＯＨ、ＮＲ^９ＯＨ、ＮＨＯＲ^９またはＮＲ^９ＯＲ^９であり；
ここで、式ＸＸＩＩＩａおよびＸＸＩＩＩｂにおいて、ＵがＳであるもしくはＲ^８がＳＲ^９である一方、またはＵがＳであるおよびＲ^８がＳＲ^９である両方であり；
ここで、式ＸＸＩＩＩｃにおいて、少なくとも１つのＵはＳであり；
Ｗは、ＣＨ、ＮまたはＣＲ^９であり；
Ｚは、ＣＨ、ＮまたはＣＲ^９であり；
各Ｒ^９は、独立して、メチル、トリフルオロメチル、フルオロ、ヨード、アルケニル、アルキニル、ビニル、アリル、ハロゲン、ハロゲン化アルキル、ヒドロキシルアルキル、アシル、脂質、ゲラニル、１つ以上の同一であるまたは異なるＲ^１０で置換されてもよいＣ_１－２２アルキルであり；
各Ｒ^１０は、独立して、アルキル、ジュウテロ、ハロゲン、ニトロ、シアノ、ヒドロキシ、アミノ、メルカプト、ホルミル、カルボキシ、アルカノイル、カルバモイル、アルコキシ、アルキルチオ、アルキルアミノ、（アルキル）_２アミノ、アルキルスルフィニル、アルキルスルホニル、アリールスルホニル、カルボシクリル、アリール、またはヘテロシクリルから選択され；
脂質は、本明細書に記載されている通りであり；
Ｙは、ＯまたはＳであり；
Ｙ^１は、ＯアリールまたはＢＨ_３ ^－Ｍ^＋であり；
Ｙ^２は、ＯＨまたはＢＨ_３ ^－Ｍ^＋であり；
Ｒ_５は、アルキル、分岐アルキルまたはシクロアルキルであり；
アリールは、本明細書に記載されている通りであり；
Ｒ_６は、Ｃ_１－２２アルコキシ、またはＣ_１－２２アルキル、アルキル、分岐アルキル、シクロアルキルもしくはアルキオキシであり；
Ｒ_７は、アリール、ヘテロアリール、置換アリール、脂質、Ｃ_１－２２アルコキシ、Ｃ_１－２２アルキル、Ｃ_２－２２アルケニル、Ｃ_２－２２アルキニルまたは置換ヘテロアリールである。

is selected from one of
each U is independently O, S, NH, ^NR9 , NHOH, ^NR9OH , ^{NHOR9 , or NR9OR9 ;
R8} is OH, SH, _NH2 , ^OR9 , ^SR9 , ^NHR9 , NHOH, ^NR9OH , ^{NHOR9 or NR9OR9 ;}
wherein in formula XXIIIa and XXIIIb, either U is S or R ⁸ is SR ⁹ , or both U is S and R ⁸ is SR ⁹ ;
wherein in formula XXIIIc, at least one U is S;
W is CH, N or ^CR9 ;
Z is CH, N or ^CR9 ;
each R ⁹ is independently methyl, trifluoromethyl, fluoro, iodo, alkenyl, alkynyl, vinyl, allyl, halogen, alkyl halide, hydroxyl alkyl, acyl, lipid, geranyl, C _1-22 alkyl optionally substituted with one or more of the same or different R ¹⁰ ;
each R ¹⁰ is independently selected from alkyl, deutero, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, alkanoyl, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) _2amino , alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl;
The lipid is as described herein;
Y is O or S;
^Y1 is Oaryl or _BH3 ^- M ⁺ ;
^Y2 is OH or _BH3 ^- M ⁺ ;
_R5 is alkyl, branched alkyl or cycloalkyl;
Aryl is as described herein;
R ₆ is C _1-22 alkoxy, or C _1-22 alkyl, alkyl, branched alkyl, cycloalkyl or alkyoxy;
R ₇ is aryl, heteroaryl, substituted aryl, lipid, C _1-22 alkoxy, C _1-22 alkyl, C _2-22 alkenyl, C _2-22 alkynyl or substituted heteroaryl.

Infectious diseases The compounds provided herein can be used to treat viral infectious diseases. Examples of viral infections include, but are not limited to, infections caused by RNA viruses (including negative-stranded RNA viruses, positive-stranded RNA viruses, double-stranded RNA viruses and retroviruses) or DNA viruses. All strains, types and subtypes of RNA and DNA viruses are contemplated herein.

Examples of RNA viruses include, but are not limited to, picornaviruses, including aphthoviruses (e.g., foot and mouth disease viruses O, A, C, Asia1, SAT1, SAT2, and SAT3), cardioviruses (e.g., encephalomyocarditis virus and Theiller's murine encephalomyelitis virus), enteroviruses (e.g., polioviruses 1, 2, and 3, human enteroviruses A-D, bovine enteroviruses 1 and 2, human coxsackieviruses A1-A22 and A24, human coxsackieviruses B1-B5, human echoviruses B1-B6, human endoviruses B1-B7, human endoviruses B1-B8, human endoviruses B1-B9, human endoviruses B1-B10, human endoviruses B1-B11, human endoviruses B1-B12, human endoviruses B1-B13, human endoviruses B1-B14, human endoviruses B1-B15, human endoviruses B1-B16, human endoviruses B1-B17, human endoviruses B1-B18, human endoviruses B1-B19, human endoviruses B1-B20, human endoviruses B1-B21, human endoviruses B1-B22, human endoviruses B1-B23, human endoviruses B1-B24, human endoviruses B1-B25, human endoviruses B1-B26, human endoviruses B1-B28, human endoviruses B1-B29, human endoviruses B1-B30, human endoviruses B1-B31, human endoviruses B1-B32, human endoviruses B1-B33, human endoviruses B1-B34, human endoviruses B1 Examples of viruses that can be used include human enteroviruses 1-7, 9, 11-12, 24, 27, 29-33, human enteroviruses 68-71, porcine enteroviruses 8-10, and simian enteroviruses 1-18), erboviruses (e.g., equine rhinitis virus), hepatoviruses (e.g., human hepatitis A virus and simian hepatitis A virus), kobuviruses (e.g., bovine kobuvirus and Aichi virus), parechoviruses (e.g., human parechovirus 1 and human parechovirus 2), rhinoviruses (e.g., rhinovirus A, rhinovirus B, rhinovirus C, HRV ₁₆ , HRV ₁₆ (VR-11757), HRV ₁₄ (VR-284), or HRV _1A (VR-1559), human rhinovirus 1-100, and bovine rhinovirus 1-3), and teschoviruses (e.g., porcine teschovirus).

Additional examples of RNA viruses include caliciviruses, which include noroviruses (e.g., Norwalk virus), sapoviruses (e.g., Sapporo virus), lagoviruses (e.g., rabbit hemorrhagic disease virus and European brown hare syndrome virus), and vesiviruses (e.g., swine vesicular ecchymoses virus and feline calicivirus). Other RNA viruses include astroviruses, which include mamastroviruses and abastroviruses. Togaviruses are also RNA viruses. Togaviruses include alphaviruses (e.g., chikungunya virus, Sindbis virus, Semliki Forest virus, western equine encephalitis virus, eastern Getah virus, Everglades virus, Venezuelan equine encephalitis virus, and aura virus) and rubella virus. Additional examples of RNA viruses include flaviviruses (e.g., tick-borne encephalitis virus, Tyurenii virus, Aroa virus, M virus (types 1 to 4), Kedogo virus, Japanese encephalitis virus (JEV), West Nile virus (WNV), Dengue virus (including genotypes 1-4), Kokobera virus, Untaya virus, Spondweni virus, Yellow fever virus, Entebbe bat virus, Modoc virus, Rio Bravo virus, cell fusion virus, Pestivirus, GB virus A, GBV-A-like virus, GB virus C, Hepatitis G virus, Hepacivirus (Hepatitis C virus (HCV)) all six genotypes), Bovine viral diarrhea virus (BVDV) types 1 and 2, and GB virus B).

Other examples of RNA viruses are coronaviruses, including human respiratory coronaviruses such as SARS-CoV, HCoV-229E, HCoV-NL63, and HCoV-OC43. Coronaviruses also include bat SARS-like CoVs, Middle East Respiratory Syndrome coronavirus (MERS), turkey coronavirus, chicken coronavirus, feline coronavirus, and canine coronavirus. Additional RNA viruses include arteriviruses (e.g., equine arterivirus, porcine reproductive and respiratory syndrome virus, lactate dehydrogenase virus of mice, and simian hemorrhagic fever virus). Other RNA viruses include rhabdoviruses, which include lyssaviruses (e.g., rabies, Lagos bat virus, Mokola virus, Duvenhage virus, and European bat lyssavirus), vegicloviruses (e.g., VSV-Indiana, VSV-New Jersey, VSV-Alagoas, Pilivirus, Coccus virus, Maraba virus, Isfahan virus, and Chandipura virus), and ephemeroviruses (e.g., Bovine ephemeral fever virus, Adelaide River virus, and Berimer virus). Additional examples of RNA viruses include filoviruses, which include Marburg and Ebola viruses (e.g., EBOV-Z, EBOV-S, EBOV-IC, and EBOV-R).

Paramyxoviruses are also RNA viruses. Examples of these viruses are rubulaviruses (e.g., mumps, parainfluenza virus 5, human parainfluenza virus type 2, mapuera virus and butalubula virus), abulaviruses (e.g., Newcastle disease virus), lespoviruses (e.g., Sendai virus, human parainfluenza virus types 1 and 3, bovine parainfluenza virus type 3), henipaviruses (e.g., Hendra virus and Nipah virus), morbilliviruses (e.g., measles, whale morbillivirus, canine distemper virus, peste des petits ruminants virus, seal distemper virus and rinderpest virus), pneumoviruses (e.g., human respiratory syncytial virus (RSV) A2, B1 and S2, bovine respiratory syncytial virus and pneumonia virus of mice), metapneumoviruses (e.g., human metapneumovirus and avian metapneumovirus). Additional paramyxoviruses include Ferdelansvirus, Tupaiparamyxovirus, Menanglevirus, Tiomanvirus, Beilongvirus, Jvirus, Mossmanvirus, Salemvirus, and Narivavirus.

Additional RNA viruses include the orthomyxoviruses. These viruses include influenza viruses and strains (e.g., influenza A, influenza A strain A/Victoria/3/75, influenza A strain A/Puerto Rico/8/34, influenza A H1N1 (including but not limited to strains A/WS/33, A/NWS/33 and A/California/04/2009), influenza B, influenza B strain Lee, and influenza C viruses) H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3 and H10N7), and avian influenza (e.g., strains H5N1, H5N1 Duck/MN/1525/81, H5N2, H7N1, H7N7 and H9N2), Thogotovirus and Isavirus. Orthobunyaviruses (e.g., Akabane virus, California encephalitis, Cachet Valley virus, snowshoe hare virus), Nairoviruses (e.g., Nairobi sheep virus, Crimean-Congo hemorrhagic fever virus group, and Hughes virus), Phleboviruses (e.g., Candiru, Punta Toro, Rift Valley fever, Sandfly fever, Neapolitan, Tuscan, Sicilian, and Chagres), and Hantaviruses (e.g., Hantan, Dobrava, Seoul, Puumala, Sin Nombre, Bayou, Black Creek Canal, Andean, and Tottapalayam) are also RNA viruses. Arenaviruses such as lymphocytic choriomeningitis virus, Lujo virus, Lassa fever virus, Argentine hemorrhagic fever virus, Bolivian hemorrhagic fever virus, Venezuelan hemorrhagic fever virus, SABV, and WWAV are also RNA viruses. Borna disease virus is also an RNA virus. Hepatitis D (delta) virus and hepatitis E are also RNA viruses.

Additional RNA viruses include reovirus, rotavirus, birnavirus, chrysovirus, cystovirus, hypovirus, particivirus, and totovirus. Orbiviruses, such as African horse sickness virus, bluetongue virus, Changuinola virus, Chenuda virus, Chobar Canyon colipartavirus, epizootic hemorrhagic fever virus, equine encephalopathy virus, euvenangivirus, Yeri virus, Great Island virus, Lebombo virus, Olungo virus, Paliam virus, Peruvian horse sickness virus, St. Croix virus, Umatilla virus, Wadmedani virus, Worrall virus, Warrigo virus, and Wongoa virus, are also RNA viruses. Retroviruses include alpharetroviruses (e.g., Rous sarcoma virus and avian leukosis virus), betaretroviruses (e.g., mouse mammary tumor virus, Mason-Pfizer monkey virus, and Jaagsiekte sheep retrovirus), gammaretroviruses (e.g., murine leukemia virus and feline leukemia virus), deltoraretroviruses (e.g., human T-cell leukemia viruses (HTLV-1, HTLV-2), bovine leukemia virus, STLV-1, and STLV-2), epsilonretroviruses (e.g., U.S. Pat. No. 5,333,621), and the like). walleye cutaneous sarcoma virus and walleye epidermal hyperplasia virus 1), reticuloendotheliosis viruses (e.g., chicken syncytial virus), lentiviruses (e.g., human immunodeficiency virus (HIV) type 1, human immunodeficiency virus (HIV) type 2, human immunodeficiency virus (HIV) type 3, simian immunodeficiency virus, equine infectious anemia virus, feline immunodeficiency virus, caprine arthritis-encephalitis virus, and visna-maedi virus), and spumaviruses (e.g., human foamy virus and feline syncytium-forming virus).

Examples of DNA viruses include polyomaviruses (e.g., simian virus 40, simian agent 12, BK virus, JC virus, Merkel cell polyomavirus, bovine polyomavirus, and lymphoproliferative papovavirus), papillomaviruses (e.g., human papillomavirus, bovine papillomavirus), adenoviruses (e.g., adenoviruses A-F, canine adenovirus type 1, canine adenovirus type 2), circoviruses (e.g., porcine circovirus and beak and feather disease virus (BFDV)), parvoviruses (e.g., canine parvovirus), erythroviruses (e.g., adeno-associated virus types 1-8), betaparvovirus, amdovirus, densovirus, Examples of viruses that may be present include, but are not limited to, rabies, iteraviruses, brevidensoviruses, pehudensoviruses, herpesviruses 1, 2, 3, 4, 5, 6, 7, and 8 (e.g., herpes simplex virus 1, herpes simplex virus 2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, Kaposi's sarcoma-associated herpesvirus, human herpesvirus-6 variant A, human herpesvirus-6 variant B, and cercopithecian herpesvirus 1 (B virus)), poxviruses (e.g., smallpox (variola), cowpox, monkeypox, vaccinia, uasin gishu, camelpox, pseudocowpox, malignant pox, horsepox, fowlpox, turkeypox, and swinepox), and hepadnaviruses (e.g., hepatitis B and hepatitis B-like viruses). Chimeric viruses that contain portions of more than one viral genome are also contemplated herein.

In some embodiments, the disclosure relates to treating or preventing viral, bacterial, fungal, protozoan and parasitic infections. In some embodiments, the disclosure relates to a method of treating a viral infection comprising administering a compound of the invention to a subject diagnosed with, suspected of, or exhibiting symptoms of a viral infection.

Viruses are infectious agents that can typically replicate inside living cells of an organism. A virus particle (virion) usually consists of nucleic acid, a protein coat, and in some cases a lipid envelope that surrounds the protein coat. Virus shapes range from simple helical and icosahedral forms to more complex structures. Virus-encoded protein subunits self-assemble to form capsids, which generally require the presence of a viral genome. Complex viruses can encode proteins that aid in the construction of their capsids. Proteins associated with nucleic acid are known as nucleoproteins, and the association of viral capsid proteins with viral nucleic acid is called nucleocapsid.

Viruses are transmitted by a variety of methods, including direct or bodily fluid contact, e.g., blood, tears, semen, pre-seminal plasma, saliva, milk, vaginal secretions, lesions; droplet contact, fecal-oral contact, or as a result of animal bites or birth. Viruses have either DNA or RNA genes and are called DNA or RNA viruses, respectively. Viral genomes are either single-stranded or double-stranded. Some viruses contain genomes that are partially double-stranded and partially single-stranded. For viruses with RNA or single-stranded DNA, the strand is said to be either positive sense (called the plus strand) or negative sense (called the minus strand), depending on whether it is complementary to the viral messenger RNA (mRNA). Positive-sense viral RNA is identical to viral mRNA and therefore can be readily translated by the host cell. Negative-sense viral RNA is complementary to mRNA and therefore must be converted to positive-sense RNA by RNA polymerase before translation. The DNA nomenclature is similar to the RNA nomenclature in that the coding strand for a viral mRNA is its complement (negative) and the non-coding strand is a copy of it (positive).

Antigenic shift or reassortment can result in new strains. Viruses undergo genetic change by several mechanisms. These include a process called genetic drift, in which individual bases in the DNA or RNA mutate to other bases. Antigenic shift occurs when there is a major change in the genome of the virus. This can be the result of recombination or reassortment. RNA viruses often exist as quasi-species or swarms of viruses with the same but slightly different genomic nucleoside sequences.

The genetic material within a virus and the way in which it is replicated varies among different types of viruses. Genomic replication of most DNA viruses takes place in the nucleus of the cell. If the cell has the appropriate receptors on its surface, these viruses enter the cell by fusion with the cell membrane or by endocytosis. Most DNA viruses are completely dependent on the host DNA and RNA synthetic and RNA processing machinery. Replication usually takes place in the cytoplasm. RNA viruses typically use their own RNA replicase enzymes to make copies of their genome.

The Baltimore classification of viruses is based on the mechanism of mRNA production. Viruses must generate mRNA from their genomes to make proteins and replicate themselves, but different mechanisms are used to accomplish this. Viral genomes can be single-stranded (ss) or double-stranded (ds) RNA or DNA, and may or may not use reverse transcriptase (RT). Additionally, ssRNA viruses can be either sense (plus) or antisense (minus). This classification separates viruses into seven groups: I, dsDNA viruses (e.g., adenoviruses, herpesviruses, poxviruses); II, ssDNA viruses (positive sense DNA) (e.g., parvoviruses); III, dsRNA viruses (e.g., reoviruses); IV, ssRNA viruses (positive sense RNA) (e.g., picornaviruses, togaviruses); V, ssRNA viruses (negative sense RNA) (e.g., orthomyxoviruses, rhabdoviruses); VI, ssRNA-RT viruses (positive sense RNA) with a DNA intermediate in their life cycle (e.g., retroviruses); and VII, dsDNA-RT viruses (e.g., hepadnaviruses).

Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family) that causes acquired immune deficiency syndrome (AIDS). Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA viruses. Upon entry of a target cell, the viral RNA genome is converted to double-stranded DNA by virally encoded reverse transcriptase. This viral DNA is then integrated into cellular DNA along with host cell cofactors by virally encoded integrase. There are two species of HIV. HIV-1 is sometimes named LAV or HTLV-III.

HIV primarily infects living cells in the human immune system, such as helper T cells (CD4+ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells. When the number of CD4+ T cells falls below a critical level, cell-mediated immunity is lost and the body becomes increasingly more susceptible to other viral or bacterial infections. Subjects with HIV typically develop malignancies that are accompanied by a progressive failure of the immune system.

The viral envelope is composed of two layers of phospholipids taken from the membrane of the human cell when the newly formed virus particle buds from the cell. Embedded in the viral envelope are proteins from the host cell and an HIV protein known as Env. Env contains the glycoproteins gp120 and gp41. The RNA genome consists of structural markers (LTR, TAR, RRE, PE, SLIP, CRS and INS) and nine genes that code for 19 proteins (gag, pol, and env, tat, rev, nef, vif, vpr, vpu, and a tenth, tev, which is sometimes a fusion of tat, env and rev). Three of these genes, gag, pol and env, contain the information needed to make the structural proteins for the new virus particle. HIV-1 diagnosis is typically performed using antibodies in ELISA, Western blot or immunoaffinity assays, or by nucleic acid tests (e.g., viral RNA or DNA amplification).

HIV is typically treated with a combination of antiviral agents, such as two nucleoside-analog reverse transcription inhibitors and one non-nucleoside-analog reverse transcription inhibitor or protease inhibitor. This three-drug combination is commonly known as a triple cocktail. In certain embodiments, the disclosure relates to treating a subject diagnosed with HIV by administering a pharmaceutical composition disclosed herein in combination with two nucleoside-analog reverse transcription inhibitors and one non-nucleoside-analog reverse transcription inhibitor or protease inhibitor.

In certain embodiments, the disclosure relates to treating a subject by administering the compounds disclosed herein, emtricitabine, tenofovir, and efavirenz. In certain embodiments, the disclosure relates to treating a subject by administering the compounds disclosed herein, emtricitabine, tenofovir, and raltegravir. In certain embodiments, the disclosure relates to treating a subject by administering the compounds disclosed herein, emtricitabine, tenofovir, ritonavir, and darunavir. In certain embodiments, the disclosure relates to treating a subject by administering the compounds disclosed herein, emtricitabine, tenofovir, ritonavir, and atazanavir.

Banana lectin (BanLec or BanLec-1) is one of the predominant proteins in the flesh of ripe bananas and has binding specificity for mannose and mannose-containing oligosaccharides. BanLec binds to the HIV-1 envelope protein gp120. In certain embodiments, the disclosure relates to treating viral infections such as HIV by administering compounds disclosed herein in combination with banana lectin.

Hepatitis C virus is a single-stranded, positive-sense RNA virus. It is the only known member of the Hepacivirus genus in the Flaviviridae family. There are six major genotypes of Hepatitis C virus, designated by numbers. Hepatitis C virus particles consist of a core of genetic material (RNA) surrounded by an icosahedral protective shell and further wrapped in a lipid envelope. Two viral envelope glycoproteins, E1 and E2, are embedded in the lipid envelope. The genome consists of a single open reading frame that is translated to produce a single protein. This large preprotein is subsequently cleaved by cellular and viral proteases into smaller proteins that allow viral replication in the host cell or assemble into mature viral particles, e.g., E1, E2, NS2, NS3, NS4, NS4A, NS4B, NS5, NS5A and NS5B.

HCV leads to inflammation of the liver and chronic infection leads to cirrhosis. Most people with hepatitis C infection have the chronic form. Diagnosis of HCV can occur through nucleic acid analysis of the 5'-noncoding region. ELISA assays can be performed to detect hepatitis C antibodies and RNA assays to determine viral load. Subjects infected with HCV may present with symptoms of abdominal pain, ascites, dark urine, fatigue, generalized pruritus, jaundice, fever, nausea, pale or clay-colored stools, and vomiting.

Therapeutic agents in some cases can suppress the virus for an extended period of time. A typical drug therapy is a combination of interferon alpha and ribavirin. The subject can receive injections of pegylated interferon alpha. Genotypes 1 and 4 are less responsive to interferon-based treatment than other genotypes (2, 3, 5, and 6). In certain embodiments, the disclosure relates to treating a subject with HCV by administering a compound disclosed herein to a subject who is symptomatic or has been diagnosed with HCV. In certain embodiments, the compound is administered in combination with interferon alpha and another antiviral agent, such as ribavirin, and/or a protease inhibitor, such as telaprevir or boceprevir. In certain embodiments, the subject has been diagnosed with genotype 2, 3, 5, or 6. In other embodiments, the subject has been diagnosed with genotype 1 or 4.

In certain embodiments, the subject has been diagnosed with the virus by nucleic acid detection or viral antigen detection. Cytomegalovirus (CMV) belongs to the Betaherpesvirinae subfamily of the Herpesviridae. In humans, it is commonly known as HCMV or human herpesvirus 5 (HHV-5). Herpes viruses typically share the characteristic ability to remain latent in the body for long periods of time. HCMV infection can be life-threatening for patients who are immunocompromised. In certain embodiments, the disclosure relates to methods of treating a subject diagnosed with cytomegalovirus or preventing cytomegalovirus infection by administration of a compound disclosed herein. In certain embodiments, the subject is immunocompromised. In typical embodiments, the subject is an organ transplant recipient undergoing hemodialysis, diagnosed with cancer, receiving immunosuppressants, and/or diagnosed with HIV infection. In certain embodiments, the subject may be diagnosed with cytomegalovirus hepatitis causing fulminant hepatic failure, cytomegalovirus retinitis (inflammation of the retina can be detected by ophthalmoscopy), cytomegalovirus colitis (inflammation of the large intestine), cytomegalovirus pneumonitis, cytomegalovirus esophagitis, cytomegalovirus mononucleosis, polyradiculopathy, transverse myelitis, and subacute encephalitis. In certain embodiments, the compounds disclosed herein are administered in combination with an antiviral agent such as valganciclovir or ganciclovir. In certain embodiments, the subject undergoes regular serological monitoring.

HCMV infection in pregnant subjects can lead to congenital abnormalities. Congenital HCMV infection occurs when the mother suffers from a primary infection (or reactivation) during pregnancy. In certain embodiments, the disclosure relates to methods of treating pregnant subjects diagnosed with cytomegalovirus or preventing cytomegalovirus infection in subjects at risk of trying to become pregnant or currently pregnant by administering a compound disclosed herein.

Subjects infected with CMV typically develop antibodies to the virus. A number of laboratory tests have been developed to detect these antibodies to CMV. The virus can be cultured from specimens obtained from urine, throat swabs, bronchial washings, and tissue samples to detect active infection. PCR can be used to monitor viral load in CMV-infected subjects. The CMV pp65 antigenemia test is an immunoaffinity-based assay to identify the pp65 protein of cytomegalovirus in peripheral blood leukocytes. CMV should be suspected if a patient has symptoms of infectious mononucleosis but has negative test results for mononucleosis and Epstein-Barr virus, or if they show signs of hepatitis but have negative test results for hepatitis A, B, and C. Viral cultures can be performed any time the subject is symptomatic. Laboratory tests for antibodies to CMV can be performed to determine if the subject already has a CMV infection.

Enzyme-linked immunosorbent assay (or ELISA) is the most commonly available serological test for measuring antibodies to CMV. Results can be used to determine whether acute infection in the infant, prior infection, or passively acquired maternal antibodies are present. Other tests include various fluorescent assays, indirect hemagglutination, (PCR), and latex agglutination. ELISA techniques for CMV-specific IgM are available.

Hepatitis B virus is a hepadnavirus. The virus particle, (virion), consists of an outer lipid envelope and an icosahedral nucleocapsid core made of proteins. The genome of HBV is made of circular DNA, but the DNA is not completely double-stranded. One end of the strand is linked to the viral DNA polymerase. The virus replicates through an RNA intermediate form by reverse transcription. Replication typically takes place in the liver where it causes inflammation (hepatitis). The virus spreads in the blood where virus-specific proteins and their corresponding antibodies are found in infected people. Blood tests for these proteins and antibodies are used to diagnose the infection.

Hepatitis B virus gains entry into cells by endocytosis. Because the virus reproduces via RNA made by host enzymes, viral genomic DNA must be transferred to the cell nucleus by host chaperones. The partially double-stranded viral DNA is then rendered fully double-stranded and transformed into covalently closed circular DNA (cccDNA) that serves as a template for transcription of viral mRNA. The virus is divided into four major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes present on its envelope protein, and into eight genotypes (A-H) according to the overall nucleotide sequence variation of the genome.

Hepatitis B surface antigen (HBsAg) is typically used to screen for the presence of this infection. It is the first detectable viral antigen that appears during infection. However, early in infection, this antigen may not be present, and it may be undetectable later in infection if it has been eliminated by the host. Infectious virions contain an internal "core particle" that encapsulates the viral genome. The icosahedral core particle is made of a core protein alternatively known as the Hepatitis B core antigen or HBcAg. IgM antibodies against the Hepatitis B core antigen (anti-HBc IgM) can be used as a serological marker. Hepatitis B e antigen (HBeAg) may appear. The presence of HBeAg in the host's serum is associated with a high rate of viral replication. Certain variants of the Hepatitis B virus do not produce the "e" antigen.

If the host is able to clear the infection, HBsAg typically becomes undetectable, followed by IgG antibodies against hepatitis B surface and core antigens (anti-HBs and anti-HBc IgG). The time between the clearance of HBsAg and the appearance of anti-HBs is called the gap time. People who are negative for HBsAg but positive for anti-HBs have either cleared the infection or have been previously vaccinated. Individuals who remain HBsAg positive for at least six months are considered to be hepatitis B carriers. Carriers of the virus may have chronic hepatitis B, reflected by elevated serum alanine aminotransferase levels and liver inflammation that can be identified by biopsy. Nucleic acid (PCR) tests have been developed to detect and measure the amount of HBV DNA in clinical specimens.

Acute infection with Hepatitis B virus is associated with acute viral hepatitis, which typically begins with symptoms of general ill health, loss of appetite, nausea, vomiting, body aches, mild fever, dark urine, and then progresses to the development of jaundice. Chronic infection with Hepatitis B virus may be either asymptomatic or may be associated with chronic inflammation of the liver (chronic hepatitis) possibly leading to cirrhosis. Having chronic Hepatitis B infection increases the incidence of hepatocellular carcinoma (liver cancer).

During HBV infection, the host immune response causes both hepatocellular injury and viral clearance. The adaptive immune response, particularly virus-specific cytotoxic T lymphocytes (CTLs), contributes to the majority of liver injury associated with HBV infection. CTLs eliminate the virus by killing infected cells and by producing antiviral cytokines that can clear HBV from viable hepatic parenchymal cells. Although liver injury is initiated and mediated by CTLs, antigen-nonspecific inflammatory cells can exacerbate CTL-induced immunopathology, and activated platelets at the site of infection can facilitate the accumulation of CTLs in the liver.

The therapeutic agent can stop the virus from replicating, thus minimizing liver damage. In certain embodiments, the disclosure relates to a method of treating a subject diagnosed with HBV by administering a compound disclosed herein. In certain embodiments, the subject is immunocompromised. In certain embodiments, the compound is administered in combination with another antiviral agent, such as lamivudine, adefovir, tenofovir, telbivudine and entecavir, and/or the immune system modulators interferon alpha-2a and pegylated interferon alpha-2a (Pegasys). In certain embodiments, the disclosure relates to preventing HBV infection in an immunocompromised subject at risk for infection by administering a pharmaceutical composition disclosed herein and, optionally, one or more antiviral agents. In certain embodiments, the subject is at risk for infection because the subject's sexual partner has been diagnosed with HBV.

The compounds of the present invention include abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, type III interferon, type II interferon, type I interferon, lamivudine, lopinavir, loviride, mamivudine, lopinavir, loviride, ramivudine ... It can be administered in combination with a second antiviral agent such as laviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, sofosvovir, stavudine, telaprevir, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine zalcitabine, zanamivir or zidovudine and combinations thereof.

In certain embodiments, one of the following compounds is administered together with the second antiviral agent described above:

Also provided is a method for treating HCV infection in a subject. The method comprises administering a compound of this invention providing at least two direct acting antiviral agents (DAAs), with or without ribavirin, for a duration of 12 weeks or less, or another duration as described herein. In one embodiment, the duration of treatment is 12 weeks or less. In another embodiment, the duration of treatment is 8 weeks or less. Preferably, the two or more direct acting antiviral agents (DAAs), with or without ribavirin, are administered in an amount effective to provide a sustained virologic response (SVR) or achieve another desired measure of efficacy in the subject. The subject does not receive interferon during the treatment regimen. In other words, in one embodiment, the method excludes administration of interferon to the subject, thereby avoiding side effects associated with interferon. In some embodiments, the method further includes administering to the subject an inhibitor of cytochrome P-450 (e.g., ritonavir) to improve one or more pharmacokinetics or bioavailability of the DAA.

In another aspect, a method for treating HCV infection in a subject is provided. The method comprises administering to the subject (a) a protease inhibitor, (b) at least one polymerase inhibitor, at least one of which is a polymerase of the invention and combinations thereof, with or without (c) ribavirin and/or (d) an inhibitor or cytochrome P-450, for a duration of 12 weeks or less or another duration as described herein (e.g., the treatment regimen can last for a duration of 8 weeks or less). Preferably, the compound is administered in an amount effective to provide a high rate of SVR or another measure of efficacy in the subject. As a non-limiting example, the compound can be co-formulated and administered once daily, with the treatment regimen preferably lasting for 8 weeks or 6 weeks.

In yet another aspect, a method is provided for treating a population of subjects having HCV infection. The method comprises administering to the subjects at least two DAAs, with or without ribavirin, where one of the DAAs is a compound of this invention, for a duration of no more than 12 weeks, or 8 weeks, or 6 weeks. Preferably, the at least two DAAs are administered to the subjects in an amount effective to produce an SVR or another measure of efficacy in at least about 70% of the population, preferably at least 90% of the population.

In the methods described above, as well as those described herein below, the DAA can be selected from the group consisting of a protease inhibitor, a nucleoside or nucleotide polymerase inhibitor (one of which is provided herein), a non-nucleoside polymerase inhibitor, an NS3B inhibitor, an NS4A inhibitor, an NS5A inhibitor, an NS5B inhibitor, a cyclophilin inhibitor, and combinations of any of the foregoing. For example, in some embodiments, the DAA used in the methods comprises or consists of at least one HCV protease inhibitor and at least one HCV polymerase inhibitor provided herein.

At least one of the HCV polymerase inhibitors is one of the compounds of this invention (described herein). By way of example, the compounds of this invention may be administered in a total daily dose of about 100 mg to about 250 mg, or may be administered once daily in a dose of about 150 mg to about 250 mg.

In some embodiments, the at least two DAAs include at least one HCV polymerase inhibitor of the present invention and at least one NS5A inhibitor. By way of example, the polymerase inhibitor of the present invention can be administered in a total daily dose of about 100 mg to about 250 mg, and the NS5A inhibitor can be administered in a total daily dose of about 25 mg to about 200 mg. Ritonavir (or another cytochrome P-450 3A4 inhibitor) can be co-administered to improve the pharmacokinetics and bioavailability of the compounds.

In the methods described above, as well as those described herein, the DAAs with or without ribavirin can be administered in any effective dosing scheme and/or frequency, for example, they can each be administered daily. Each DAA can be administered either separately or in combination, and each DAA can be administered at least once a day, at least twice a day, or at least three times a day. Similarly, ribavirin can be administered at least once a day, at least twice a day, or at least three times a day, either separately or in combination with one or more of the DAAs. In some preferred embodiments, the compound is administered once a day.

In some embodiments, the technology provides a method for treating HCV infection comprising administering at least two DAAs, with or without ribavirin, to a subject in need thereof for a duration of 12 weeks or 8 weeks or 6 weeks or less, wherein the subject is not administered interferon during said duration. In some embodiments, the at least two DAAs, with or without ribavirin, are administered in an amount effective to result in SVR. Some methods further comprise administering to the subject an inhibitor of cytochrome P450. In some embodiments, the duration is 8 weeks or less.

In yet another embodiment, the at least two direct acting antiviral agents comprise a combination of drugs selected from the group consisting of: a compound of this invention and one or more of ABT-450 and/or ABT-267 and/or ABT-333; a novel compound of this invention and one or more of the compounds disclosed in US 2010/0144608; US 61/339,964; US 2011/0312973; WO 2009/039127; US 2010/0317568; 2012/151158; US 2012/0172290; WO 2012/092411; WO 2012/087833; WO 2012/083170; WO 2009/039135; US 2012 any of the compounds disclosed in WO 2010/075376; US 7,9105,95; WO 2010/120935; WO 2010/111437; WO 2010/111436; US 2010/0168384 or US 2004/0167123; any of the compounds of this invention and one or more of simeprevir and/or GSK805; any of the compounds of this invention and one or more of asunaprevir and/or daclatasvir and/or BMS-325; any of the compounds of this invention and one or more of GS- 9451, and/or ledipasvir and/or sofosbuvir and/or GS-9669; a compound of this invention and one or more of ACH-2684 and/or ACH-3102 and/or ACH-3422; a compound of this invention and one or more of boceprevir and/or MK-8742; a compound of this invention and one or more of faldaprevir and/or deleobvir; a compound of this invention and PPI-668; a compound of this invention and one or more of telaprevir and/or VX-135; a compound of this invention and one or more of samatasvir and/or IDX-437; a compound of this invention and PSI- 7977 and/or PSI-938, a compound of this invention and BMS-790052 and/or BMS-650032; a compound of this invention and GS-5885 and/or GS-9451; a compound of this invention and GS-5885, GS-9190 and/or GS-9451; a combination of a compound of this invention and BI-201335 and/or BI-27127; a combination of a compound of this invention and telaprevir and/or VX-222; a combination of a compound of this invention and PSI-7977 and/or TMC-435; and a combination of a compound of this invention and danoprevir and/or R7128.

In yet another embodiment, the at least two direct acting antivirals include a compound of this invention in combination with PSI-7977 and/or BMS-790052 (daclatasvir). In yet another embodiment, the at least two direct acting antivirals include a compound of this invention in combination with PSI-7977 and/or BMS-650032 (asunaprevir). In yet another embodiment, the at least direct acting antivirals include a compound of this invention in combination with PSI-7977, BMS-650032 (asunaprevir) and/or BMS-790052 (daclatasvir). The compounds of this invention can either be added to these combinations or used to replace the listed polymerases.

In another aspect, the technology features a combination of at least two DAAs for use in treating HCV infection, where the duration of the treatment regimen is 12 weeks or less (e.g., the duration is 12 weeks; or the duration is 11, 10, 9, 8, 7, 6, 5, 4, or 3 weeks). The treatment includes administering at least two DAAs to a subject infected with HCV. The duration of the treatment is 12 weeks, and can last, for example, 8 weeks or less (e.g., the duration is 8 weeks; or the duration is 7, 6, 5, 4, or 3 weeks). The treatment can include administering ribavirin, but not interferon. If one of the DAAs requires pharmacokinetic enhancement, the treatment can also include administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat). At least two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once a day and another DAA can be administered twice a day. In another example, two DAAs are administered once a day. In yet another example, two DAAs are co-formulated in a single composition and administered simultaneously (e.g., once a day). As a non-limiting example, the patient being treated can be infected with HCV genotype 1, such as genotype 1a or 1b. As another non-limiting example, the patient can be infected with HCV genotype 2 or 3. As yet another non-limiting example, the patient can be an HCV treatment-naïve patient, an HCV treatment-experienced patient, an interferon non-responder (e.g., a non-responder, partial responder, or relapser), or not a candidate for interferon treatment.

In another aspect, the present technology features a combination of at least two DAAs for use in treating HCV infection, wherein said combination includes a compound of this invention in combination with a compound selected from:
Combinations of PSI-7977 and/or PSI-938;
combinations of BMS-790052 and/or BMS-650032;
Combinations of GS-5885 and/or GS-9451;
combinations of GS-5885, GS-9190 and/or GS-9451;
combinations of BI-201335 and/or BI-27127;
in combination with telaprevir and/or VX-222;
Combinations of PSI-7977 and/or TMC-435;
combination of danoprevir and/or R7128;
combinations of ABT-450 and/or ABT-267 and/or ABT-333;
one or more of the following protease inhibitors: ABT450, simeprevir, asunaprevir, GS-9451, ACH-2684, boceprevir, MK-5172, faldaprevir and telaprevir;
one or more of the following NS5A inhibitors: ABT-267, GSK805, daclatasvir, ledipasvir, GS-5816, ACH-3102, MK-8742, PPI-668 and samatasvir;
One or more of the following non-nuc NS5B inhibitors: ABT-333, TMC055, BMS-325, GS-9669 and Deleobuvir.

In one embodiment, the compound of the invention used in the above combination therapy is 1911, 2023 or 2024. In a currently preferred embodiment, the novel compound of the invention used in the above combination therapy is 2023. One or more of 1911, 2033 and 2024 may be selected from the group consisting of ABT-450, ABT-267 and/or ABT-333 and/or the compounds disclosed in US 2010/0144608; US 61/339,964; US 2011/0312973; WO 2009/039127; US 2010/0317568; 2012/151158; US 2012/0172290; WO 2012/092411; WO 2012/087833; WO 2012/083170; WO 2009/0 39135; US2012/0115918; WO2012/051361; WO2012/009699; WO2011/156337; US2011/0207699; WO2010/075376; US7,9105,95; WO2010/120935; WO2010/111437; WO2010/111436; US2010/0168384 or US2004/0167123.

In yet another aspect, the present technology features a combination of at least two DAAs for use in treating HCV infection, wherein said combination comprises a compound of this invention in a combination selected from the following:
ABT-450 and/or ABT-267 and/or ABT-333 and/or US 2010/0144608; US 61/339,964; US 2011/0312973; WO 2009/039127; US 2010/0317568; 2012/151158; US 2012/0172290; WO 2012/092411; WO 2012/087833; WO 2012/083170; WO 2009/ 039135; US 2012/0115918; WO 2012/051361; WO 2012/009699; WO 2011/156337; US 2011/0207699; WO 2010/075376; US 7,9105,95; WO 2010/120935; WO 2010/111437; WO 2010/111436; compounds disclosed in US 2010/0168384 or US 2004/0167123;
combinations of PSI-797 and/or BMS-790052;
combinations of PSI-7977 and/or BMS-650032;
combinations of PSI-7977, BMS-790052 and/or BMS-650032;
Combinations of INX-189 and/or BMS-790052;
A combination of INX-189 and/or BMS-650032; or a combination of INX-189, BMS-790052 and/or BMS-650032.

In yet another aspect, the present technology features a combination of PSI-7977 or at least two DAAs for use in treating HCV infection, wherein said combination includes a compound of this invention and a combination of a compound selected from the following:
Combination of mericitabine and/or danoprevir;
A combination of daclatasvir and/or BMS-791325; and a combination of PSI-7977 and/or GS-5885.

The treatment involves administering PSI-7977 or a DAA combination to a subject infected with HCV.

In yet another aspect, the present technology features a compound of this invention with PSI-7977 or a combination of at least two DAAs for use in treating HCV infection, wherein said combination includes a combination selected from the following:
Combination of mericitabine and/or danoprevir;
Combinations of INX-189, daclatasvir and/or BMS-791325; and combinations of PSI-7977 and/or GS-5885.

The treatment involves administering PSI-7977 or a DAA combination to a subject infected with HCV.

In yet another aspect, the present technology features a combination of at least two DAAs for use in treating HCV infection, wherein said combination includes a compound of this invention and a combination selected from the following:
combination of tegobuvir and/or GS-9256;
Combinations of BMS-791325, asunaprevir and/or daclatasvir; and combinations of TMC-435 and/or daclatasvir.

The treatment involves administering a DAA combination to a subject infected with HCV.

In yet another aspect, the technology features a combination of a compound of the invention with PSI-7977 and/or BMS-790052 for use in treating HCV infection. The treatment includes administering the DAA combination to a subject infected with HCV.

In yet another aspect, the present technology features a combination of a compound of the present invention with PSI-7977 and/or TMC-435 for use in treating HCV infection.

In yet another aspect, the present technology features a combination of a compound of the present invention with danoprevir and/or mericitabine for use in treating HCV infection.

In yet another aspect, the technology features a combination of a compound of the invention with daclatasvir and/or BMS-791325 for use in treating HCV infection. The treatment includes administering a DAA combination to a subject infected with HCV.

In yet another aspect, the technology features a combination of a compound of the invention with PSI-7977 and/or GS-5885 for use in treating HCV infection. The treatment includes administering the DAA combination to a subject infected with HCV.

The duration of the treatment regimen is 16 weeks or less (e.g., the duration is 16 weeks; or the duration is 14, 12, or 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 week). The treatment includes administering ribavirin, but does not include administering interferon. If one of the DAAs requires pharmacokinetic enhancement, the treatment may include administering ritonavir or another CYP3A4 inhibitor (e.g., cobicistat). The two DAAs can be administered simultaneously or sequentially. For example, one DAA can be administered once daily and the other DAA can be administered twice daily. In another example, the two DAAs are administered once daily. In yet another example, the two DAAs are co-formulated in a single composition and administered simultaneously (e.g., once daily). As a non-limiting example, the patient being treated may be infected with HCV genotype 1, such as genotype 1a or 2b. As another non-limiting example, the patient may be infected with HCV genotype 2 or 3. In yet another non-limiting example, the patient may be an HCV treatment naive patient, an HCV treatment experienced patient, an interferon non-responder (e.g., a non-responder), or may not be a candidate for interferon treatment.

In yet another embodiment of this aspect of the invention, the at least two DAAs include an HCV protease inhibitor and an HCV polymerase inhibitor of the invention. The treatment can last for 12 weeks or less, such as, for example and without limitation, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for example, a treatment-naive patient. The subject can also be a treatment-experienced patient or an interferon non-responder (e.g., a non-responder). Preferably, the subject being treated is infected with HCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the at least two DAAs include a compound of this invention together with an HCV protease inhibitor and a non-nucleoside or non-nucleotidic HCV polymerase inhibitor. The treatment can last for 12 weeks or less, for example and without limitation, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks. Preferably, the treatment lasts for 12 weeks. The treatment can also last for 8 weeks. The subject being treated can be, for example, a treatment-naive patient. The subject can also be a treatment-experienced patient or an interferon non-responder (e.g., a non-responder). Preferably, the subject being treated is infected with HCV genotype 1, e.g., HCV genotype 1a. As another non-limiting example, the subject being treated is infected with HCV genotype 3.

In yet another embodiment of this aspect of the invention, the DAA comprises a compound of this invention together with an HCV protease inhibitor and an HCV NS5A inhibitor.

In yet another embodiment of this aspect of the invention, the at least two DAAs include an HCV polymerase inhibitor and an HCV NS5A inhibitor of the invention.

In yet another embodiment of this aspect of the invention, the DAA comprises a compound of this invention and an HCV non-nucleoside or non-nucleotide polymerase inhibitor and an HCV NS5A inhibitor.

In yet another embodiment of this aspect of the invention, the DAA can include an HCV nucleoside or nucleotide polymerase inhibitor of the invention and an HCV NS5A inhibitor.

In yet another embodiment of this aspect of the invention, the at least two DAAs include a compound of this invention together with PSI-7977 and/or TMC-435.

In yet another embodiment of this aspect of the invention, the DAA comprises a compound of this invention together with PSI-7977 and/or daclatasvir.

In yet another embodiment of this aspect of the invention, the DAA comprises a compound of this invention together with PSI-7977 and/or GS-5885.

In yet another embodiment of this aspect of the invention, the DAA comprises a compound of this invention together with mericitabine and/or danoprevir.

In yet another embodiment of this aspect of the invention, the DAA comprises a compound of this invention together with BMS-790052 and/or BMS-650032.

In yet another embodiment of this aspect of the invention, the DAA comprises a compound of this invention and INX-189, daclatasvir and/or BMS-791325.

The treatment regimens of the present technology generally constitute a complete treatment regimen, i.e., no subsequent interferon-containing regimens are contemplated. Thus, the treatments or uses described herein generally do not include any subsequent interferon-containing treatments.

In one aspect of the disclosure, an "infection" or "bacterial infection" is an infection caused by Acinetobacter spp, Bacteroides spp, Burkholderia spp, Campylobacter spp, Chlamydia spp, Chlamydophila spp, Clostridium spp, Enterobacter spp, Enterococcus spp, Escherichia spp, or any of the following: spp, Fusobacterium spp, Gardnerella spp, Haemophilus spp, Helicobacter spp, Klebsiella spp, Legionella spp, Moraxella spp, Morganella spp, Mycoplasma spp, Neisseria spp, Peptococcus spp, spp), Peptostreptococcus spp, Proteus spp, Pseudomonas spp, Salmonella spp, Serratia spp., Staphylococcus spp, Streptococcus spp, Stenotrophomonas spp, or Ureaplasma spp.

In one embodiment of the disclosure, an "infection" or "bacterial infection" is an infection caused by Acinetobacter baumannii, Acinetobacter haemolyticus, Acinetobacter junii, Acinetobacter johnsonii, Acinetobacter Iwoffi, Bacteroides bivius, Bacteroides fragilis, or any of the following: fragilis, Burkholderia cepacia, Campylobacter jejuni, Chlamydia pneumoniae, Chlamydia urealyticus, Chlamydia pneumoniae, Clostridium difficile, Enterobacter aerogenes, Enterobacter cloacae cloacae, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Gardnerella vaginalis, Haemophilus parainfluenzae, Haemophilus influenzae, Helicobacter pylori, Klebsiella pneumoniae pneumoniae), Legionella pneumophila, Methicillin-resistant Staphylococcus aureus, Penicillin-susceptible Staphylococcus aureus, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Penicillin-resistant Streptococcus pneumoniae pneumoniae, penicillin-susceptible Streptococcus pneumoniae, Peptostreptococcus magnus, Peptostreptococcus micros, Peptostreptococcus anaerobius, Peptostreptococcus asaccharolyticus, Peptostreptococcus prevotiii prevotii, Peptostreptococcus tetradius, Peptostreptococcus vaginalis, Proteus mirabilis, Pseudomonas aeruginosa, Quinolone-resistant Staphylococcus aureus, Quinolone-resistant Staphylococcus epidermis, Salmonella typhi typhi, Salmonella paratyphi, Salmonella enteritidis, Salmonella typhimurium, Serratia marcescens, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus agalactiae agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Stenotrophomonas maltophilia, Ureaplasma urealyticum, Vancomycin-resistant Enterococcus faecium, Vancomycin-resistant Enterococcus faecalis, Vancomycin-resistant Staphylococcus aureus aureus), vancomycin-resistant Staphylococcus epidermis, mycobacterium tuberculosis, clostridium perfringens, klebsiella oxytoca, neisseria miningitidis, proteus vulgaris, or coagulase-negative staphylococci (Staphylococcus lugdunensis). It refers to an infection caused by Staphylococcus lugdunensis, Staphylococcus capitis, Staphylococcus hominis, or Staphylococcus saprophytic.

In one embodiment of the disclosure, "infection" or "bacterial infection" refers to an aerobe, an obligate anaerobe, a facultative anaerobe, a gram-positive bacterium, a gram-negative bacterium, a gram-variant bacterium, or an atypical respiratory pathogen.

In some embodiments, the disclosure relates to treating bacterial infections, such as gynecological infections, respiratory tract infections (RTIs), sexually transmitted infections, or urinary tract infections.

In some embodiments, the disclosure relates to treating bacterial infections, such as infections caused by drug-resistant bacteria.

In some embodiments, the disclosure relates to treating bacterial infections such as community-acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, gonococcal cervicitis, gonococcal urethritis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, and infections caused by drug-resistant bacteria such as penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and vancomycin-resistant Enterococcus, syphilis, ventilator-associated pneumonia, intraperitoneal infections, gonorrhea, meningitis, tetanus, or tuberculosis.

In some embodiments, the disclosure relates to treating fungal infections such as infections caused by Tinea versicolor, Microsporum, Trichophyton, Epidermophyton, candidiasis, cryptococcosis, or aspergillosis.

In some embodiments, the disclosure relates to treating infections caused by protozoa, including but not limited to malaria, amebiasis, giardiasis, toxoplasmosis, cryptosporidiosis, trichomoniasis, leishmaniasis, sleeping sickness, or dysentery.

Certain compounds disclosed herein are useful for preventing or treating malaria parasite infection in a subject and/or preventing, treating and/or alleviating complications and/or symptoms associated therewith, and can then be used in the preparation of medicaments for the treatment and/or prevention of such diseases. Malaria can be caused by Plasmodium falciparum, P. vivax, P. ovale, or P. malariae.

In one embodiment, the compound is administered after the subject has been exposed to the malaria parasite. In another embodiment, the compounds disclosed herein are administered after the subject has traveled to a country where malaria is endemic.

The compound or the pharmaceutical composition described above may also be used in combination with one or more other therapeutically useful substances selected from the group including antimalarials such as quinolines (e.g., quinine, chloroquine, amodiaquine, mefloquine, primaquine, tafenoquine); peroxide antimalarials (e.g., artemisinin, artemether, artesunate); pyrimethamine-sulfadoxine antimalarials (e.g., fansidar); hydroxynaphthoquinones (e.g., atovaquone); acrolin-type antimalarials (e.g., pyronaridine); and antiprotozoal agents such as ethylstibamine, hydroxystilbamidine, pentamidine, stilbamidine, quinapyramine, puromycin, propamidine, nifurtimox, melarsoprol, nimorazole, nifuroxime, and aminitrozole.

In embodiments, the compounds disclosed herein are chloroquine, artemesin, quingaos, 8-aminoquinolines, amodiaquine, artether, artemether, artemisinin, artesunate, artesunic acid, artelic acid, atovaquone, azithromycin, biguanides, chloroquine phosphate, chlorproguanil, cycloguanil, dapsone, desbutylhalofantrine, desipramine, doxycycline, dihydrofolate reductase inhibitors, dipyridamole, It may be used in combination with one additional drug selected from the group consisting of halofantrine, haloperidol, hydroxychloroquine sulfate, imipramine, mefloquine, penfluridol, phospholipid inhibitors, primaquine, proguanil, pyrimethamine, pyronaridine, quinine, quinidine, quinacrine artemisinin, sulfonamides, sulfones, sulfadoxine, sulfalene, tafenoquine, tetracycline, tetrandrine, triazines, salts or mixtures thereof.

Cancer In an exemplary embodiment, the disclosure relates to a method of treating cancer comprising administering to a patient a compound disclosed herein. In some embodiments, the disclosure relates to a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, for use in treating cancer.

In some embodiments, the disclosure relates to a compound disclosed herein, or a pharma- tically acceptable salt thereof, as defined herein for use in the treatment of breast, colorectal, lung (including small cell lung carcinoma, non-small cell lung carcinoma, and bronchoalveolar carcinoma), and prostate cancer.

In some embodiments, the disclosure relates to a compound disclosed herein or a pharma- tically acceptable salt thereof, as defined herein, for use in the treatment of cancers of the bile duct, bone, bladder, head and neck, kidney, liver, gastrointestinal tissue, esophagus, ovary, endometrium, pancreas, skin, testis, thyroid, uterus, cervix and vulva, as well as leukemia (including ALL and CML), multiple myeloma and lymphoma.

In some embodiments, the disclosure relates to a compound disclosed herein or a pharma- tically acceptable salt thereof, as defined herein, for use in the treatment of lung cancer, prostate cancer, melanoma, ovarian cancer, breast cancer, endometrial cancer, renal cancer, gastric cancer, sarcoma, head and neck cancer, tumors of the central nervous system and metastases thereof, as well as for the treatment of glioblastoma.

In some embodiments, the compounds disclosed herein can be used in the clinic either alone as single agents or in combination with other clinically relevant agents. The compounds can also prevent potential cancer resistance mechanisms that may arise due to mutations in a range of genes.

The anti-cancer treatment defined herein can be applied as a sole therapy or can involve, in addition to the disclosed compounds, conventional surgery or radiation therapy or chemotherapy. Such chemotherapy can include one or more of the following categories of anti-tumor agents:
(i) Antiproliferative/antineoplastic agents and combinations thereof as used in medical oncology, such as alkylating agents (e.g. cisplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan and nitrosoureas); antimetabolites (e.g. 5-fluorouracil and antifolates such as gemcitabine, tegafur, raltitrexed, methotrexate, fluoropyrimidines such as cytosine arabinoside and hydroxyurea); antitumor antibiotics (e.g. adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, anthracyclines such as mitomycin-C, dactinomycin, and mithramycin); mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as taxol and taxotere); and topoisomerase inhibitors (e.g., etoposide and teniposide, epipodophyllotoxins such as amsacrine, topotecan, and camptothecin); and proteosome inhibitors (e.g., bortezomib [Velcade®]); and the drug anagrelide [Agrylin®]; and the drug alpha-interferon;
(ii) Cytostatic agents, such as antiestrogens (e.g. tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), estrogen receptor down-modulators (e.g. fulvestrant), antiandrogens (e.g. bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or agonists (e.g. goserelin, leuprorelin and buserelin), progestogens (e.g. megestrol acetate), aromatase inhibitors (e.g. as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride;
(iii) agents that inhibit cancer cell invasion (e.g., metalloproteinase inhibitors such as marimastat and inhibitors of urokinase plasminogen activator receptor function);
(iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (e.g., the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab), farnesyltransferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, for example: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib), and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033), such as inhibitors of the platelet derived growth factor family and such as inhibitors of the hepatocyte growth factor family, such as inhibitors of phosphatidylinositol 3-kinase (PI3K) and such as inhibitors of mitogen-activated protein kinase kinase (MEK1/2) and such as inhibitors of protein kinase B (PKB/Akt), such as inhibitors of the Src tyrosine kinase family and/or the Abelson (Abl) tyrosine kinase family, such as dasatinib (BMS-354825) and imatinib mesylate (Gleevec™); and any agent which modifies STAT signaling;
(v) antiangiogenic agents, such as those that inhibit the effects of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab [Avastin™]), and compounds that work by other mechanisms (e.g., linomide, an inhibitor of integrin ocvβ3 function, and angiostatin);
(vi) vascular damaging agents, such as combretastatin A4;
(vii) antisense therapeutics, e.g., those directed to the targets listed above, such as anti-ras antisense;
(viii) gene therapy approaches, including approaches to replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene directed enzyme prodrug therapy) approaches such as those using cytosine deaminase, thymidine kinase or bacterial nitroreductase enzymes, and approaches to increase patient resistance to chemotherapy or radiotherapy such as multidrug resistance gene therapy; and (ix) immunotherapy approaches, including ex vivo and in vivo approaches to increase the immunogenicity of patient tumor cells, for example transfection of cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to reduce T cell anergy, approaches using transfected immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumor cell lines, and approaches using anti-idiotypic antibodies, as well as approaches using the immunomodulatory drugs thalidomide and lenalidomide (Revlimid®).

Such conjoint treatments can be accomplished via simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this disclosure, or pharma- ceutically acceptable salts thereof, within the dosage ranges previously described herein, and the other pharma- ceutically active agent within its approved dosage range.

Formulations The pharmaceutical compositions disclosed herein may be in the form of pharma- ceutically acceptable salts, as generally described below. Some preferred, but non-limiting, examples of suitable pharma- ceutically acceptable organic and/or inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acetic acid and citric acid, as well as other pharma-ceutically acceptable acids known per se (see the literature references referred to below).

When the disclosed compounds contain an acidic group as well as a basic group, the disclosed compounds can form inner salts, and such compounds are within the scope of the disclosure. When the disclosed compounds contain a hydrogen-donating heteroatom (e.g., NH), the disclosure also encompasses salts and/or isomers formed by migration of a hydrogen atom to a basic group or atom within the molecule.

Pharmaceutically acceptable salts of the compounds include their acid addition and base salts. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzeate, hydrochloride/chloride, hydrobromate/bromide, hydroiodide/iodide, Included are isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases can also be formed, such as hemisulfate and hemicalcium salts. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), incorporated herein by reference.

The compounds described herein can be administered in the form of prodrugs. Prodrugs can include covalently bonded carriers that release the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compound in such a way that the modification is cleaved, either by routine manipulation or in vivo, relative to the parent compound. Prodrugs include, for example, compounds in which a hydroxyl group is bonded to any group that cleaves to form a free hydroxyl group when administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol functional groups in the compound. Methods for structuring compounds as prodrugs are known, for example, in Testa and Mayer, Hydrolysis in Drug and Prodrug Metabolism, Wilcy (2006). Typical prodrugs form active metabolites by conversion of the prodrug by hydrolysis of hydrolases, amides, lactams, peptides, carboxylic acid esters, epoxides, or cleavage of esters of inorganic acids. Ester prodrugs have been shown to be readily broken down in the body to release the corresponding alcohol. See, e.g., Imai, Drug Metab Pharmacokinet. (2006) 21(3):173-85, entitled "Human carboxylesterase isozymes: catalytic properties and rational drug design."

Pharmaceutical compositions for use in the present disclosure typically contain an effective amount of the compound and a suitable pharma- ceutical acceptable carrier. The preparations can be prepared in a manner known per se, which usually involves mixing at least one compound according to the disclosure with one or more pharma- ceutical acceptable carriers and, if desired, in combination with other pharma- ceutical active compounds under sterile conditions, if necessary. Reference is made to U.S. Pat. Nos. 6,372,778, 6,369,086, 6,369,087 and 6,372,733 and the further literature described above, as well as to standard handbooks such as the latest edition of Remington's Pharmaceutical Sciences.

Generally, for pharmaceutical use, the compounds can be formulated as a pharmaceutical preparation comprising at least one compound and at least one pharma- ceutically acceptable carrier, diluent or excipient, and optionally one or more further pharma- ceutically active compounds.

The pharmaceutical preparations of the disclosure are preferably in unit dosage form and can be suitably packaged, for example, in boxes, blisters, vials, bottles, sachets, ampoules, or any other suitable single-dose or multi-dose holders or containers (which can be appropriately labeled); optionally with one or more pamphlets containing product information and/or instructions for use. Generally, such unit dosages contain between 1 mg and 1000 mg, and usually between 5 mg and 500 mg, e.g., about 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg per unit dosage.

The compounds can be administered by a variety of routes, including oral, ocular, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, depending primarily on the particular preparation used. The compounds are generally administered in an "effective amount", which means any amount of compound that, at appropriate doses, is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which it is administered. Typically, depending on the condition to be prevented or treated and the route of administration, such an effective amount is usually between 0.01 mg and 1000 mg per kilogram of patient body weight per day, more frequently between 0.1 mg and 500 mg, e.g., between 1 mg and 250 mg, e.g., about 5 mg, 10 mg, 20 mg, 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, which can be administered as a single daily dose divided into one or more daily doses. The amount(s) to be administered, the route of administration, and further treatment regimes can be determined by the treating clinician depending on factors such as the age, sex and general condition of the patient, and the nature and severity of the disease/symptom to be treated. Reference is made to U.S. Patent Nos. 6,372,778, 6,369,086, 6,369,087 and 6,372,733 and further references mentioned above, as well as to standard handbooks such as the latest edition of Remington's Pharmaceutical Sciences.

For oral administration forms, the compounds can be mixed with suitable additives such as excipients, stabilizers or inert diluents and made into suitable administration forms such as tablets, coated tablets, hard capsules, aqueous, alcoholic or oily solutions by customary methods. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this case, the preparation can be carried out both as dry and wet granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. As immediate release tablets, these compositions can contain microcrystalline cellulose, dibasic calcium phosphate, starch, magnesium stearate and lactose, and/or other excipients, binders, fillers, disintegrants, diluents and lubricants known in the art.

When administered by nasal aerosol or inhalation, the compositions can be prepared according to techniques well known in the art of pharmaceutical formulations and can be prepared as a solution in saline with benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical formulations for administration in the form of an aerosol or spray are, for example, solutions, suspensions or emulsions of the disclosed compounds or their physiologically tolerable salts in a pharma- ceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If necessary, the formulations can additionally contain other pharmaceutical auxiliaries, such as surfactants, emulsifiers and stabilizers, as well as propellants.

For subcutaneous or intravenous administration, the compounds are, if desired, made into solutions, suspensions or emulsions together with substances customary therefor, such as solubilizers, emulsifiers or further auxiliaries. The compounds can be lyophilized, and the lyophilizates obtained can also be used, for example, for the production of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, such as ethanol, propanol, glycerol, sugar solutions, such as glucose or mannitol solutions, or mixtures of the various solvents mentioned. Injectable solutions or suspensions can be formulated according to known techniques using suitable non-toxic parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting agents and suspending agents, such as sterile oils, non-irritating oils, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

When administered rectally in the form of a suppository, the formulation can be prepared by mixing the compound of formula I with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at room temperature but release the drug by liquefying and/or dissolving in the rectal cavity.

It is contemplated that in certain embodiments, these compositions may be extended release formulations. A typical extended release formulation utilizes an enteric coating. Typically, a barrier is applied to an oral medication that controls the location in the digestive system where it is absorbed. The enteric coating prevents release of the medication before it reaches the small intestine. Enteric coating agents include polymers of polysaccharides such as maltodextrin, xanthan, scleroglucan dextran, starch, alginates, pullulan, hyaluronic acid, chitin and chitosan; other natural polymers such as proteins (albumin, gelatin, etc.), poly-L-lysine; sodium poly(acrylic acid); poly(hydroxyalkyl methacrylates) (e.g. poly(hydroxymethyl methacrylate)); carboxypolymethylenes (e.g. Carbopol™); carbomer; polyvinylpyrrolidone; gums such as guar gum, gum arabic, gum karaya, gum ghatti, locust bean gum, tamarind gum, gellan gum, tragacanth gum, agar, pectin and gluten; poly(vinyl alcohols), ... ethylene vinyl alcohol; polyethylene glycol (PEG); and cellulose ethers such as hydroxymethylcellulose (HMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose (MC), ethylcellulose (EC), carboxyethylcellulose (CEC), ethylhydroxyethylcellulose (EHEC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxypropylmethyl-cellulose (HPMC), hydroxypropylethylcellulose (HPEC) and sodium carboxymethylcellulose (Na-CMC); as well as copolymers and/or (simple) mixtures of any of the above polymers. Some of the polymers described above may be further crosslinked via standard techniques.

The choice of polymer is determined by the nature of the active ingredient/drug used in the disclosed compositions and the desired rate of release. It will be recognized by those skilled in the art that, particularly in the case of, for example, HPMC, a higher molecular weight generally provides a slower rate of drug release from the composition. Furthermore, in the case of HPMC, different degrees of substitution of methoxyl and hydroxypropoxyl groups will result in changes in the release rate of the drug from the composition. In this regard and as noted above, it may be desirable to provide the disclosed compositions in the form of a coating in which the polymeric carrier is provided, for example, via a blend of two or more polymers of different molecular weights, to produce a particular required or desired release profile.

Microspheres of polylactide, polyglycolide, and their copolymer poly(lactide-co-glycolide) can be used to form sustained release protein delivery systems. Proteins can be entrapped in poly(lactide-co-glycolide) microsphere depots by a number of methods, including forming a water-in-oil emulsion using an aqueous protein and an organic solvent-based polymer (emulsion method), forming a solid-in-oil suspension using a solid protein dispersed in a solvent-based polymer solution (suspension method), or dissolving the protein in a solvent-based polymer solution (dissolution method). Attaching poly(ethylene glycol) to the protein (PEGylation) can increase the in vivo half-life of circulating therapeutic proteins and reduce the chance of an immune response.

Liposomal suspensions (including liposomes targeted to viral antigens) can also be prepared by conventional methods for producing pharma- ceutically acceptable carriers, which may be suitable for delivery of the free nucleoside, acyl nucleoside or phosphate ester prodrug forms of the nucleoside compounds according to the invention.

It is recognized that the nucleosides of the present invention have several chiral centers and can exist and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. The present invention should be understood to encompass any racemic, optically active, diastereomeric, polymorphic or stereoisomeric forms of the compounds of the present invention, or mixtures thereof, that possess the useful properties described herein. It is well known in the art how to prepare optically active forms (e.g., by resolution of racemic forms, by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using chiral stationary phases).

The carbons of nucleosides are chiral, and their non-hydrogen substituents (the base and CHOR group, respectively) can be either cis (on the same side) or trans (on opposite sides) relative to the sugar ring system. The four optical isomers are therefore represented by the following configurations (when the sugar moiety is oriented in a horizontal plane so that the oxygen atom is recessed): cis (both groups are "up", corresponding to the configuration of naturally occurring β-D nucleosides), cis (both groups are "down", the non-naturally occurring β-L configuration), trans (the C2' substituent is "up" and the C4' substituent is "down"), and trans (the C2' substituent is "down" and the C4' substituent is "up".) "D-nucleosides" are cis nucleosides in the natural configuration, and "L-nucleosides" are cis nucleosides in the non-naturally occurring configuration.

Similarly, most amino acids are chiral (designated as L or D, where the L enantiomer is the naturally occurring configuration) and can exist as separate enantiomers.

Examples of methods for obtaining optically active materials are known in the art and include at least the following: i) Physical separation of crystals - a technique in which macroscopic crystals of individual enantiomers are manually separated. This technique can be used provided that crystals of the separate enantiomers exist, i.e. the material is a conglomerate and the crystals are visually distinct; ii) simultaneous crystallization - a technique in which the individual enantiomers are crystallized separately from a solution of the racemate, which is only possible if the latter is a conglomerate in the solid state; iii) enzymatic resolution - a technique in which partial or complete separation of the racemate is due to the different rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis - a synthetic technique in which at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis - a synthetic technique in which the desired enantiomer is synthesized from an achiral precursor under conditions that generate asymmetry (i.e. chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomeric separation - a technique in which a racemate is reacted with an enantiomerically pure reagent (chiral auxiliary) that converts the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to their now well-defined structural differences, and the chiral auxiliary is subsequently removed to yield the desired enantiomer; vii) primary and secondary asymmetric transformations - techniques in which equilibration of the diastereomers from the racemate in favor of a solution of the diastereomer from the desired enantiomer, or preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium, ultimately converting essentially all of the material from the desired enantiomer to a crystalline diastereomer. The desired enantiomer is then released from the diastereomer; viii) kinetic resolution - this technique refers to achieving partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantioselective synthesis from non-racemic precursors - a synthetic technique in which the desired enantiomer is obtained from a non-chiral starting material and the stereochemical integrity is not or only minimally compromised over the course of the synthesis; x) chiral liquid chromatography - a technique in which the enantiomers of a racemate are separated in a liquid mobile phase due to their differential interactions with the stationary phase. The stationary phase can be made of chiral material or the mobile phase can contain additional chiral material to induce different interactions; xi) chiral gas chromatography - a technique in which the racemate is volatilized and the enantiomers are separated due to different interactions of the enantiomers in a gaseous mobile phase in a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents - a technique in which the enantiomers are separated due to preferential dissolution of one enantiomer in a particular chiral solvent; xiii) transport across chiral membranes - a technique in which the racemate is contacted with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as a concentration difference or pressure difference causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass. Chiral chromatography, including simulated moving bed chromatography, is used in one embodiment. A wide variety of chiral stationary phases are commercially available.

Some of the compounds described herein contain olefinic double bonds and, unless otherwise specified, are meant to include both E and Z geometric isomers.

In addition, some of the nucleosides described herein may exist as tautomers, such as keto-enol tautomers. The individual tautomers as well as mixtures thereof are intended to be encompassed within the compounds of the present invention.

[Example 1]
Conjugate Preparation Mono- and diphosphate prodrugs have been prepared by several groups. See Jessen et al., Bio reversible Protection of Nucleoside Diphosphates, Angewandte Chemie-International Edition English 2008, 47(45), 8719-8722, incorporated herein by reference. To prevent cleavage of the P-O-P anhydride bond, side groups can be utilized that rapidly fragment (e.g., bis-(4-acyloxybenzyl)-nucleoside diphosphates (BAB-NDPs) that are deacylated by endogenous esterases) to generate a negative charge on the second phosphate. Routledge et al., Synthesis, Bioactivation and Anti-HIV Activity of 4-Acyloxybenzyl-bis(nucleoside-5'-yl) Phosphates, Nucleosides & Nucleotides 1995, 14(7), 1545-1558 and Meier et al., Comparative study of bis(benzyl)phosphate triesters of 2',3'-dideoxy-2',3'-didehydrothymidine (d4T) and See also cycloSal-d4TMP-hydrolysis, mechanistic insights and anti-HIV activity, Antiviral Chemistry and Chemotherapy 2002, 13, 101-114. When this occurs, the P-O-P anhydride bond is not susceptible to cleavage and the remaining protecting groups can then be used for their final degradation to generate the nucleoside diphosphate.

Another method for preparing diphosphate and monothiodiphosphate prodrugs is shown in Figure 5. Using standard coupling conditions, the sphingolipid-nucleoside monophosphate prodrugs are prepared. The corresponding diphosphate prodrugs can be prepared according to the protocol shown in Figure 5, as well as by the methods described in Smith et al., Substituted Nucleotide Analogs., incorporated herein by reference in their entireties. U.S. Patent Application 2012/0071434; Skowronska et al., Reaction of Oxophosphorane-Sulfenyl and Oxophosphorane-Selenium Chlorides with Dialkyl Trimethylsilyl Phosphites-Novel Synthesis of Compounds Containing a Sulfur or Selenium Bridge Between 2 Phosphoryl Centers, Journal of the Chemical Society-Perkin Transactions 1 1988, 8, 2197-2201; Dembinski et al., An Expedient Synthesis of Symmetrical Terra-Alkyl Mono-thiopyrophosphates, Tetrahedron Letters 1994, 35(34), 6331-6334; Skowronska et al., Novel Synthesis of Symmetrical Tetra-Alkyl Monothiophosphates, Tetrahedron Letters 1987, 28(36), 4209-4210; and Chojnowski et al., Methods of Synthesis of 0,0-Bis TrimethylSilyl Phosphorothiolates. Synthesis-Stuttgart 1977, 10, 683-686.

[Example 2]
Activity of 2-Fluoro Nucleosides Ribonucleoside analogs, when activated to their corresponding triphosphates, inhibit RNA-dependent RNA viral replication by acting as competitive substrate inhibitors of the virally encoded RdRp. Compounds in this therapeutic class are useful in treating viruses found in, but not limited to, the Arenaviridae, Bunyaviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae and Togaviridae viral families. It is contemplated that certain compounds disclosed herein have advantages such as a high genetic barrier for antiviral resistance; broad spectrum activity within the viral family; and high oral bioavailability with targeted delivery to the site of infection.

Nucleoside analogs were designed with 2'-alpha-fluorine substituents to mimic natural ribonucleosides. The C-F bond length (1.35 Å) is similar to the C-O bond length (1.43 Å), and the fluorine is a hydrogen-bond acceptor that replaces the fluorine substituent with an isopolar and isosteric hydroxyl group. Unlike ribonucleoside analogs currently in clinical trials to treat HCV infection, in certain embodiments, the 2',3'-dideoxy-2'-fluoronucleoside analogs encompassed by this disclosure lack a 3'-hydroxyl group and are therefore absolute chain terminators of viral replication. When the nucleosides are converted to their triphosphates, they act as competitive substrate inhibitors of the virally encoded RdRp. Following incorporation of the chain terminator into the nascent RNA, viral replication ceases. One advantage of absolute chain terminators is that they are not mutagenic to the host when treating chronic diseases.

[Example 3]
NS5B RNA-dependent RNA polymerase reaction conditions Compounds were assayed for inhibition of NS5B-δ21 from HCV GT-1bCon-1. Reactions contained purified recombinant enzyme, 1 u/μL negative-stranded HCV IRES RNA template, and 1 μM NTP substrates including either [ ³² P]-CTP or [ ³² P]-UTP. Assay plates were incubated at 27° C. for 1 hour before quenching. [ ³² P] incorporation into macromolecular products was determined by filter binding.

The table below shows the activity of selected analog triphosphates against HCV NS5B polymerase.

[Example 4]

[Example 5]

[Example 6]

[Example 7]

[Example 8]

[Example 9]

[Example 10]

[Example 11]
Results from VEEV replicon assay

[Example 12]

[Example 13]
Synthesis of Sphingolipids and Derivatives The preparation of sphingolipids is provided in PCT/US12/57448, which is incorporated herein by reference in its entirety.

[Example 14]
General synthesis of 2',3'-dideoxy-2'-P-substituted-2'-α-fluoronucleosides

試薬および条件：ａ）ＮａＮＯ_２、ＨＣｌ_（ａｑ）；ｂ）ＢＨ_３ ＳＭｅ_２；ｃ）ＴＢＤＰＳＣｌ、ＤＭＡＰ、ピリジン；ｄ）ｉ．ＬｉＨＭＤＳ、ｉｉ．ＲＸ（Ｘ＝ＣＩ、Ｂｒ、Ｉなど）；ｅ）ｉ．ＴＢＳＯＴｆ、Ｅｔ_３Ｎ、ｉｉ．ＮＦＳｉ；ｆ）ＤＩＢＡＬ；ｇ）Ａｃ_２Ｏ、ＤＭＡＰ；ｈ）ＨＭＰＴ、ＣＣｌ_４

Reagents and conditions: a) _NaNO2 , HCl _(aq) ; b) _BH3SMe2 ; c) TBDPSCl, DMAP, _pyridine ; d) i. LiHMDS, ii. RX (X = CI, Br, I, etc.); e) i. TBSOTf, _Et3N , ii. NFSi; f) DIBAL; g) _Ac2O , DMAP; h) HMPT, _CCl4.

[Example 15]
Base coupling and deprotection

試薬および条件：ａ）シリル化塩基、ＴＭＳＯＴｆ、ＤＣＥ；ｂ）ＴＢＡＦ、ＴＨＦ；ｃ）ヌクレオベース、ＴＤＡ－１、ＫＯＨ、ＭｅＣＮ

Reagents and conditions: a) silylated base, TMSOTf, DCE; b) TBAF, THF; c) nucleobase, TDA-1, KOH, MeCN

[Example 16]
Synthesis of 2',3'-dideoxy-2'-α-fluoronucleosides

試薬および条件：ａ）ＮａＮＯ_２、ＨＣｌ_（ａｑ）；ｂ）ＢＨ_３ ＳＭｅ_２；ｃ）ＴＢＤＰＳＣｌ、ＤＭＡＰ、ピリジン；ｄ）ｉ．ＬｉＨＭＤＳ、ｉｉ．ＮＦＳｉ；ｅ）ＤＩＢＡＬ；ｆ）Ａｃ_２Ｏ、ＤＭＡＰ；ｇ）ＨＭＰＴ、ＣＣｌ_４

Reagents and conditions: a) _NaNO2 , HCl _(aq) ; b) _BH3SMe2 ; c) TBDPSCl, DMAP, pyridine; d) i. LiHMDS, ii _. NFSi; e) DIBAL; f) _Ac2O , DMAP; g) HMPT, _CCl4.

[Example 17]
Base coupling and deprotection

試薬および条件：ａ）シリル化塩基、ＴＭＳＯＴｆ、ＤＣＥ；ｂ）ＴＢＡＦ、ＴＨＦ；ｃ）ヌクレオベース、ＴＤＡ－１、ＫＯＨ、ＭｅＣＮ

Reagents and conditions: a) silylated base, TMSOTf, DCE; b) TBAF, THF; c) nucleobase, TDA-1, KOH, MeCN

[Example 18]
1-Chloro-2,3-dideoxy-2-fluoro-5-tert-butyldimethylsilyl ribose 17

A mixture of 2,3-dideoxy-2-fluoro-5-tert-butyldimethylsilyl ribose (840 mg, 2.24 mmol) and carbon tetrachloride (1.55 g, 10.09 mmol) in anhydrous toluene (15 mL) at -50°C was treated dropwise over 35 minutes with a solution of hexamethyl phosphorous triamide (440 mg, 2.69 mmol) in toluene (15 mL). The mixture was stirred while gradually warming to 0°C and maintained at this temperature for 3 hours. After cooling to -20°C, the mixture was diluted with cold toluene (50 mL) and quenched by the dropwise addition of cold brine (5 mL at -10°C). After 10 minutes, the organic layer was separated and washed again with cold brine (10 mL). After drying over sodium sulfate, the organic phase was filtered and concentrated by rotary evaporation (bath set at 20° C.) to give crude 17 (900 mg) with an α:β ratio of 9:1. The crude material was used in the next step without further purification.
^1H NMR (400MHz, chloroform-d) δ 7.65-7.58 (m, 5H), 7.46-7.32 (m, 7H), 6.28 (d, J=4.1 Hz, 1H), 5.36 (td, J=8.4, 4.2 Hz, 1H), 5.22 (td, J=8.3, 4.1 Hz, 1H), 4.55 (ddt, J=7.6, 5.2, 2.8 Hz, 1H), 3.78 (ddd, J=11.5, 2.7, 1.8 Hz, 1H), 3.60 (dd, J=11.5, 2.8 Hz, 1H), 2.44-2.35 (m, 2H).

[Example 19]
Synthesis of 2',3'-dideoxy-2'-α-methyl-2'-α-fluoronucleosides

試薬および条件：ａ）ＮａＮＯ_２、ＨＣｌ（水溶液）；ｂ）ＢＨ_３・ＳＭｅ_２；ｃ）ＴＢＤＰＳＣｌ、ＤＭＡＰ、ピリジン；ｄ）ｉ．ＬｉＨＭＤＳ、ｉｉ．ＭｅＩ；ｅ）ｉ．ＴＢＳＯＴｆ、Ｅｔ_３Ｎ、ｉｉ．ＮＦＳｉ；ｆ）ＤＩＢＡＬ；ｇ）Ａｃ_２Ｏ、ＤＭＡＰ；ｈ）ＨＭＰＴ、ＣＣｌ_４

Reagents and conditions: a) _NaNO2 , HCl (aq); b) _BH3.SMe2 ; c) TBDPSCl, DMAP, pyridine; d) i. LiHMDS, ii. _MeI ; e) i. TBSOTf, _Et3N , ii. NFSi; f) DIBAL; g) _Ac2O , DMAP; h) HMPT, _CCl4 .

[Example 20]
Base coupling and deprotection

試薬および条件：ａ）シリル化塩基、ＴＭＳＯＴｆ、ＤＣＥ；ｂ）ＴＢＡＦ、ＴＨＦ；ｃ）核酸塩基、ＴＤＡ－１、ＫＯＨ、ＭｅＣＮ

Reagents and conditions: a) silylated base, TMSOTf, DCE; b) TBAF, THF; c) nucleobase, TDA-1, KOH, MeCN

[Example 21]
(3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-methyldihydrofuran-2(3H)-one (31).

To a solution of diisopropylamine (2.01 ml, 14.1 mmol) in dry THF (20 ml) at 0° C. under an inert atmosphere was added n-butyllithium (8.83 ml of a 1.6 M solution in hexane, 14.13 mmol). After stirring for 30 minutes, the solution was cooled to −78° C. and a solution of (4S)-4-tert-butyldiphenylsiloxymethyl-4-butanolide (5.01 g, 14.13 mmol) in dry THF (5 ml) was added dropwise over 5 minutes. After stirring for a further 30 minutes at −78° C., iodomethane (1.31 ml, 21.0 mmol) was added and the reaction vessel was removed from the ice bath. After 30 minutes at ambient temperature, deionized water (40 ml) was added to the solution and the organics were extracted with ether (3×15 ml). The combined organic layers were washed with 1M HCl (3×20 ml), washed once more with brine, and then dried over _MgSO . The crude product was purified by silica chromatography eluting with 85:15 hexanes:ethyl acetate (product Rf=0.26 in ₄ :1 hexanes:ethyl acetate) to give the final product as a white crystalline solid. The stereochemistry was established based on comparison of the NMR data with the reported data.
^1H NMR (400MHz, _CDCl3 ): δ 7.67-7.65 (m, 4H), 7.48-7.39 (m, 6H), 4.58-4.53 (m, 1H), 3.86 (dd, J = 3.2, 10.8 Hz, 1H), 3.68 (dd, J = 3.2, 11.2 Hz, 1H), 2.90-2.81 (m, 1H), 2.45 (ddd, J = 3.2, 9.2, 12.8 Hz, 1H), 1.98 (dt, J = 8.8, 12.4 Hz, 1H), 1.30 (d, J = 7.2 Hz, 3H), 1.06 (s, 9H).

[Example 22]
(3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluoro-3-methyldihydrofuran-2(3H)-one (32).

Compound 31 (0.1000 g, 0.27 mmol) was placed in a dry flask under argon and dissolved in dry DCM (5 mL). TBSOTf (0.075 mL, 0.33 mmol) was then added dropwise to the stirred DCM solution of lactone at room temperature, followed by neat triethylamine (0.057 mL, 0.41 mmol), also at room temperature. The reaction mixture was stirred under nitrogen at room temperature for 2 hours while being monitored by TLC. NFSi (0.1280 g, 0.41 mmol) was then dissolved in 2 mL of dry DCM and added dropwise to the silyl enol ether at room temperature under nitrogen. The reaction mixture turned dark red. The reaction mixture was stirred overnight. The reaction mixture was quenched with saturated NH4Cl and diluted with ether. The organic layer was washed with brine, dried over _MgSO4 , filtered and concentrated. The product was purified on silica eluting with 8:1 hexanes/ethyl acetate.
^1H NMR (400MHz, _CDCl3 ): δ 7.67-7.64 (m, 4H), 7.48-7.39 (m, 6H), 4.75-4.70 (m, 1H), 3.96 (dd, J = 3.6, 12Hz, 1H), 3.71 (dd, J = 3.6, 11.6Hz, 1H), 2.53 (ddd, J = 6.4, 14.6, 22.8Hz, 1H), 2.37 (ddd, J = 8.8, 14.6, 35.2Hz, 1H), 1.66 (d, J = 22.8Hz, 3H), 1.05 (s, 9H).

[Example 23]
(2R,3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluoro-3-methyltetrahydrofuran-2-ol (33)

Compound 33 was prepared following the procedure outlined by JOC (1998), 63, 2161-2167.
^1H NMR (400MHz, _CDCl3 ): δ 7.70-7.67 (m, 4H), 7.47-7.39 (m, 6H), 5.10 (t, J = 7.2 Hz, 1H), 4.50 (m, 1H), 3.87 (dd, J = 2.4, 11.2 Hz, 1H), 3.46 (dd, J = 2.4, 11.2 Hz, 1H), 2.27-2.11 (m, 2H), 1.57 (d, J = 21.6 Hz, 3H), 1.09 (s, 9H).

[Example 24]
(2S,3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-3-fluoro-3-methyltetrahydrofuran-2-yl acetate (34).

Compound 34 was prepared following the procedure outlined by JOC (1998), 63, 2161-2167.
^1H NMR (400MHz, _CDCl3 ): δ 7.69-7.66 (m, 4H), 7.46-7.37 (m, 6H), 6.13 (d, J = 10.4 Hz, 1H), 4.53-4.47 (m, 1H), 3.79 (dd, J = 4.4, 10.8 Hz, 1H), 3.72 (dd, J = 4.4, 11.6 Hz, 1H), 2.27-2.02 (m, 2H), 1.92 (s, 3H), 1.50 (d, J = 21.6 Hz, 3H), 1.07 (s, 9H).

[Example 25]
General Nucleobase Coupling Conditions The desired nucleobase (5 equiv.) was transferred to a dry flask under argon atmosphere and suspended in HMDS (2 mL/1 mmol of nucleobase). Catalytic ammonium sulfate (1-3 mg) was added to the reaction vessel and the suspension was refluxed for 1-3 h. During the course of the reaction, the white suspension turned clear. The reaction vessel was cooled to room temperature and excess HMDS was removed under reduced pressure. The resulting residue was dissolved in dry DCE (5 mL/1 mmol of compound 34) followed by the addition of compound 34 at room temperature. Finally, neat TMSOTf (5.5 equiv.) was added to the stirring solution. The reaction was quenched with saturated sodium bicarbonate. The organic layer was collected, dried over _MgSO4 , filtered and concentrated under reduced pressure. The desired protected nucleoside was purified on silica gel eluting with 9:1 DCM/MeOH.

[Example 26]
General deprotection conditions: A solution of the protected nucleoside in dry THF (10 ml/1 mmol of protected nucleoside) was treated with tetrabutylammonium fluoride (TBAF, 1 M solution in THF, 1.1 equivalents) and stirred at room temperature for 3 hours. The crude mixture was concentrated in vacuo and the resulting residue was purified on silica gel (0-10% methanol in dichloromethane) to give the desired nucleoside.

[Example 27]
Alternative Route for the Synthesis of 2',3'-Dideoxy-2'-β-Substituted-2'-α-Fluoronucleosides

試薬および条件：ａ）ＡｃＣｌ、ピリジン、ＤＣＭ；ｂ）ＴＣＤＩ、ピリジン、ＤＣＭ；ｃ）Ｂｕ_３ＳｎＨ、ＡＩＢＮ；ｄ）Ａｃ_２Ｏ、ＡｃＯＨ、Ｈ_２ＳＯ_４；ｅ）ｉ．シリル化塩基、ＴＭＳＯＴｆ、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｆ）ＢｚＣｌ；ｇ）ＤＭＰ；ｈ）ＲＬｉまたはＲＭｇＢｒ；ｉ）ＤＡＳＴ；ｊ）ＮＨ_３、ＭｅＯＨ

Reagents and conditions: a) AcCl, pyridine, DCM; b) TCDI, pyridine, DCM; c) _Bu3SnH , AIBN; d) Ac2O _, AcOH _{, H2SO4} ; e) i. silylation base, TMSOTf, ii. _K2CO3 , MeOH; f) BzCl; g) DMP; h) RLi or RMgBr; i) DAST; j) _NH3 , MeOH _.

[Example 28]
Alternative Route to 2',3'-Dideoxy-2'-α-Fluoronucleosides

試薬および条件：ａ）ＡｃＣｌ、ピリジン、ＤＣＭ；ｂ）ＴＣＤＩ、ピリジン、ＤＣＭ；ｃ）Ｂｕ_３ＳｎＨ、ＡＩＢＮ；ｄ）Ａｃ_２Ｏ、ＡｃＯＨ、Ｈ_２ＳＯ_４；ｅ）ｉ．シリル化塩基、ＴＭＳＯＴｆ、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｆ）ＢｚＣｌ；ｇ）ＤＭＰ；ｈ）ＮａＢＨ_４；ｉ）ＤＡＳＴ；ｊ）ＮＨ_３、ＭｅＯＨ

Reagents and conditions: a) AcCl, pyridine, DCM; b) TCDI, pyridine, DCM; c) _Bu3SnH , AIBN; d) Ac2O _, AcOH _{, H2SO4} ; e) i. silylation base, TMSOTf, _ii . _K2CO3 , MeOH; f) BzCl; g) DMP; h) _NaBH4 ; i) DAST; j) _NH3 , MeOH.

[Example 29]
2',3'-dideoxy-2'-β-ethynyl-2'-α-fluoronucleoside

試薬および条件：ａ）ＡｃＣｌ、ピリジン、ＤＣＭ；ｂ）ＴＣＤＩ、ピリジン、ＤＣＭ；ｃ）Ｂｕ_３ＳｎＨ、ＡＩＢＮ；ｄ）Ａｃ_２Ｏ、ＡｃＯＨ、Ｈ_２ＳＯ_４；ｅ）ｉ．シリル化塩基、ＴＭＳＯＴｆ、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｆ）ＢｚＣｌ；ｇ）ＤＭＰ；ｈ）ｉ．トリメチルシリルアセチレン、ＢｕＬｉ、ｉｉ．ＮＨ_４Ｆ、ＭｅＯＨ；ｉ）ＤＡＳＴ；ｊ）ＮＨ_３、ＭｅＯＨ

Reagents and conditions: a) AcCl, pyridine, DCM; b) TCDI, pyridine, DCM; c) _Bu3SnH , AIBN; d) Ac2O _, AcOH _{, H2SO4} ; e) i. silylation base, TMSOTf, ii. _K2CO3 , MeOH; f) BzCl; g) DMP; h) i. trimethylsilylacetylene, BuLi, ii. _NH4F , MeOH; i) DAST; j) _NH3 , MeOH _.

[Example 30]
2',3'-dideoxy-2'-β-fluoromethyl-2'-α-fluoronucleoside

試薬および条件：ａ）ＡｃＣｌ、ピリジン、ＤＣＭ；ｂ）ＴＣＤＩ、ピリジン、ＤＣＭ；ｃ）Ｂｕ_３ＳｎＨ、ＡＩＢＮ；ｄ）Ａｃ_２Ｏ、ＡｃＯＨ、Ｈ_２ＳＯ_４；ｅ）ｉ．シリル化塩基、ＴＭＳＯＴｆ、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｆ）ＢｚＣｌ；ｇ）ＤＭＰ；ｈ）Ｍｅ_３Ｓ（Ｏ）Ｉ、ＮａＨ；ｉ）ＫＦ、１８－クラウン－６；ｊ）ＤＡＳＴ；ｋ）ＮＨ_３、ＭｅＯＨ

Reagents and conditions: a) AcCl, pyridine, DCM; b) TCDI, pyridine, DCM; c) _Bu3SnH , AIBN; d) Ac2O _, AcOH _{, H2SO4} ; e) i. silylation base, TMSOTf, ii. _K2CO3 , MeOH; f) BzCl; g) DMP; h) _Me3S (O)I, NaH; i) KF, 18-crown-6; j) DAST; k) _NH3 , MeOH _.

[Example 31]
2',3'-dideoxy-2'-β-difluoromethyl or trifluoromethyl-2'-α-fluoronucleosides

試薬および条件：ａ）ＡｃＣｌ、ピリジン、ＤＣＭ；ｂ）ＴＣＤＩ、ピリジン、ＤＣＭ；ｃ）Ｂｕ_３ＳｎＨ、ＡＩＢＮ；ｄ）Ａｃ_２Ｏ、ＡｃＯＨ、Ｈ_２ＳＯ_４；ｅ）ｉ．シリル化塩基、ＴＭＳＯＴｆ、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｆ）ＢｚＣｌ；ｇ）ＤＭＰ；ｈ）ＣＨＦ_２：ｉ．ＰｈＳＯ_２ＣＦ_２Ｈ、ＬｉＨＭＤＳ、ｉｉ．ＳｍＩ_２またはＣＦ_３：ＴＭＳＣＦ_３、ＴＢＡＦ；ｉ）ＤＡＳＴ；ｊ）ＮＨ_３、ＭｅＯＨ

Reagents and conditions: a) AcCl, pyridine, DCM; b) TCDI, pyridine, DCM; c) _Bu3SnH , AIBN; d) Ac2O _, AcOH _{, H2SO4} ; e) i. silylation base, _TMSOTf , ii _{. K2CO3} , MeOH; f) BzCl; g) DMP; h) _CHF2 : i _. PhSO2CF2H, LiHMDS, ii. _SmI2 or _CF3 : _TMSCF3 , TBAF; i) DAST; j) _NH3 , MeOH.

[Example 32]
Alternative Route to 2',3'-Dideoxy-2'-β-Substituted-2'-α-Fluoronucleosides

試薬および条件：ａ）ＡｃＣｌ、ピリジン、ＤＣＭ；ｂ）ＴＣＤＩ、ピリジン、ＤＣＭ；ｃ）Ｂｕ_３ＳｎＨ、ＡＩＢＮ；ｄ）ｉ．Ｈ_２ＳＯ_４、ＭｅＯＨ、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｅ）ＢｚＣｌ、ピリジン；ｆ）ＤＭＰ；ｇ）ＲＬｉまたはＲＭｇＢｒ；ｈ）ＤＡＳＴ；ｉ）Ａｃ_２Ｏ、ＡｃＯＨ、Ｈ_２ＳＯ_４；ｊ）シリル化塩基、ＴＭＳＯＴｆ；ｋ）ＮＨ_３、ＭｅＯＨ

Reagents and conditions: a) AcCl, pyridine, DCM; b) TCDI, pyridine, DCM; c) _Bu3SnH , AIBN; d) _i . _H2SO4 , MeOH, _ii . _K2CO3 , MeOH; e) BzCl, pyridine; f) DMP; g) RLi or RMgBr; h) DAST; i) _Ac2O , AcOH, _H2SO4 ; j) silylation base, TMSOTf; k) _NH3 , MeOH _.

[Example 33]
Synthesis of 2'-deoxy-2'-α-fluororibonucleosides

試薬および条件：ａ）ＴＢＤＰＳＣｌ、イミダゾール；ｂ）アセトン、ＣｕＳＯ_４、Ｈ_２ＳＯ_４；ｃ）ＫＯＨ、ＢｎＣｌ；ｄ）ＣＳＡ、ＭｅＯＨ；ｅ）ｉ．Ｔｆ_２Ｏ、ｉｉ．ＴＢＡＦ；ｆ）９０％ＴＦＡ（水溶液）；ｇ）Ａｃ_２Ｏ、ＤＭＡＰ；ｈ）ＨＭＰＴ、ＣＣｌ_４

Reagents and conditions: a) TBDPSCl, imidazole; b) acetone, _CuSO4 , _H2SO4 ; c) KOH, BnCl; d) CSA, MeOH; e) i _. Tf2O, ii _. TBAF; f) 90% TFA (aq); g) Ac2O _, DMAP; h) HMPT, _CCl4

[Example 34]
Base coupling and deprotection

試薬および条件：ａ）シリル化塩基、ＴＭＳＯＴｆ、ＤＣＥ；ｂ）ＢＣｌ_３、ＤＣＭ；ｃ）核酸塩基、ＴＤＡ－１、ＫＯＨ、ＭｅＣＮ

Reagents and conditions: a) silylated base, TMSOTf, DCE; b) BCl ₃ , DCM; c) nucleobase, TDA-1, KOH, MeCN.

[Example 35]
Synthesis of 2'-deoxy-2'-β-substituted-2'-α-fluororibonucleosides

試薬および条件：ａ）ｉ．Ｉ_２、アセトン、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｂ）ＫＯＨ、ＢｎＣｌ；ｃ）Ｈ_２ＳＯ_４、ＭｅＯＨ；ｄ）ＤＭＰ；ｅ）ＲＬｉまたはＲＭｇＢｒ；ｆ）ＤＡＳＴ；ｇ）Ｈ_２ＳＯ_４、Ｈ_２Ｏ；ｈ）Ａｃ_２Ｏ、ＤＭＡＰ；ｉ）ＨＭＰＴ、ＣＣｌ_４

Reagents and conditions: a) i. _I2 , _acetone , ii. _K2CO3 , MeOH; b) KOH, BnCl; c) _H2SO4 , MeOH; d) DMP; e) RLi or RMgBr; f) DAST; g _{) H2SO4} , _H2O ; h) _Ac2O , DMAP; i) HMPT, _{CCl4 .}

[Example 36]
Base coupling and deprotection

試薬および条件：ａ）シリル化塩基、ＴＭＳＯＴｆ、ＤＣＥ；ｂ）ＢＣｌ_３、ＤＣＭ；ｃ）核酸塩基、ＴＤＡ－１、ＫＯＨ、ＭｅＣＮ

Reagents and conditions: a) silylated base, TMSOTf, DCE; b) BCl ₃ , DCM; c) nucleobase, TDA-1, KOH, MeCN.

[Example 37]
Alternative synthesis for 2'-deoxy-2'-α-fluororibonucleosides

試薬および条件：ａ）ｉ．Ｉ_２、アセトン、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｂ）ＫＯＨ、ＢｎＣｌ；ｃ）Ｈ_２ＳＯ_４、ＭｅＯＨ；ｄ）ＤＭＰ；ｅ）ＮａＢＨ_４；ｆ）ＤＡＳＴ；ｇ）Ｈ_２ＳＯ_４、Ｈ_２Ｏ；ｈ）Ａｃ_２Ｏ、ＤＭＡＰ；ｉ）ＨＭＰＴ、ＣＣｌ_４

Reagents and conditions: a) i. _I2 , _acetone , ii. _K2CO3 , MeOH; b) KOH, BnCl _; c) _H2SO4 , MeOH; d) DMP; e) _NaBH4 ; f) DAST; g) _H2SO4 , _H2O ; h) _Ac2O , DMAP; i) HMPT, _{CCl4 .}

[Example 38]
Base coupling and deprotection

試薬および条件：ａ）シリル化塩基、ＴＭＳＯＴｆ、ＤＣＥ；ｂ）ＢＣｌ_３、ＤＣＭ；ｃ）核酸塩基、ＴＤＡ－１、ＫＯＨ、ＭｅＣＮ

Reagents and conditions: a) silylated base, TMSOTf, DCE; b) BCl ₃ , DCM; c) nucleobase, TDA-1, KOH, MeCN.

[Example 39]
Synthesis of 2'-deoxy-2'-β-fluoromethyl-2'-α-fluororibonucleosides

試薬および条件：ａ）ｉ．Ｉ_２、アセトン、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｂ）ＫＯＨ、ＢｎＣｌ；ｃ）Ｈ_２ＳＯ_４、ＭｅＯＨ；ｄ）ＤＭＰ；ｅ）ｉ．Ｍｅ_３Ｓ（Ｏ）Ｉ、ＮａＨ、ｉｉ．ＫＦ、１８－クラウン－６；ｆ）ＤＡＳＴ；ｇ）Ｈ_２ＳＯ_４、Ｈ_２Ｏ；ｈ）Ａｃ_２Ｏ、ＤＭＡＰ；ｉ）ＨＭＰＴ、ＣＣｌ_４

Reagents and conditions: a) i. _I2 , _acetone , ii. _K2CO3 , MeOH; b) KOH, BnCl; c) _H2SO4 , MeOH; d) DMP; e) i. _Me3S (O)I, NaH, ii. KF, 18-crown- ₆ ; f) DAST; g) _{H2SO4 , H2O} ; h) _Ac2O , DMAP; i) HMPT, _CCl4

[Example 40]
Base coupling and deprotection

試薬および条件：ａ）シリル化塩基、ＴＭＳＯＴｆ、ＤＣＥ；ｂ）ＢＣｌ_３、ＤＣＭ；ｃ）核酸塩基、ＴＤＡ－１、ＫＯＨ、ＭｅＣＮ

Reagents and conditions: a) silylated base, TMSOTf, DCE; b) BCl ₃ , DCM; c) nucleobase, TDA-1, KOH, MeCN.

[Example 41]
Synthesis of 2'-deoxy-2'-β-difluoromethyl or trifluoromethyl-2'-α-fluororibonucleosides

試薬および条件：ａ）ｉ．Ｉ_２、アセトン、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｂ）ＫＯＨ、ＢｎＣｌ；ｃ）Ｈ_２ＳＯ_４、ＭｅＯＨ；ｄ）ＤＭＰ；ｅ）ＣＨＦ_２：ｉ．ＰｈＳＯ_２ＣＦ_２Ｈ、ＬｉＨＭＤＳ、ｉｉ．ＳｍＩ_２またはＣＦ_３：ＴＭＳＣＦ_３、ＴＢＡＦ；ｆ）ＤＡＳＴ；ｇ）Ｈ_２ＳＯ_４、Ｈ_２Ｏ；ｈ）Ａｃ_２Ｏ、ＤＭＡＰ；ｉ）ＨＭＰＴ、ＣＣｌ_４

Reagents and conditions: a) i. _I2 , _acetone , ii. _K2CO3 , MeOH; b) KOH, BnCl; c) _{H2SO4 ,} MeOH; d) DMP _; e) CHF2: i. _PhSO2CF2H , LiHMDS, _{ii. SmI2 or CF3} : _TMSCF3 , TBAF; f) DAST; g) _H2SO4 , _H2O ; h _{) Ac2O} , DMAP; i) HMPT, _CCl4

[Example 42]
Base coupling and deprotection

試薬および条件：ａ）シリル化塩基、ＴＭＳＯＴｆ、ＤＣＥ；ｂ）ＢＣｌ_３、ＤＣＭ；ｃ）核酸塩基、ＴＤＡ－１、ＫＯＨ、ＭｅＣＮ

Reagents and conditions: a) silylated base, TMSOTf, DCE; b) BCl ₃ , DCM; c) nucleobase, TDA-1, KOH, MeCN.

[Example 43]
Alternative synthesis of 2',3'-dideoxy-2'-β-substituted-2'-α-fluoronucleosides

試薬および条件：ａ）ＴＢＳＣｌ、Ｅｔ_３Ｎ、ＤＭＡＰ；ｂ）ｉ．フェニルクロロチオノホルメート、ｉｉ．ＡＩＢＮ；ｃ）ＴＢＡＦ

Reagents and conditions: a) TBSCl, Et ₃ N, DMAP; b) i. phenyl chlorothionoformate, ii. AIBN; c) TBAF

[Example 44]
Monophosphate and Diphosphate Prodrug Synthesis

試薬および条件：ａ）クロロホスホルアミデート、イミダゾール；ｂ）ＤＩＣ、脂質－１－リン酸；ｃ）ＰＯＣｌ_３、Ｏ＝Ｐ（ＯＭｅ）_３；ｄ）ｉ．ＤＩＣ、モルホリン、ｉｉ．スフィンゴイド塩基－１－リン酸、テトラゾール

Reagents and conditions: a) chlorophosphoramidate, imidazole; b) DIC, lipid-1-phosphate; c) POCl ₃ , O═P(OMe) ₃ ; d) i. DIC, morpholine, ii. sphingoid base-1-phosphate, tetrazole.

[Example 45]
N-tert-Butyloxycarbonyl-sphingosine (124)

Prepared according to Boumendjel, Ahcene and Miller, Stephen Journal of Lipid Research 1994, 35, 2305.

A mixture of sphingosine (450 mg, 1.50 mmol) and di-tert-butyl dicarbonate (0.656 g, 3.01 mmol) in methylene chloride (100 mL) at 4° C. was treated dropwise with diisopropylethylamine (0.53 mL, 3.01 mmol). After gradually warming to room temperature, the mixture was stirred for an additional 12 h and then diluted with methylene chloride (100 mL) followed by washing with water (30 mL) and brine (30 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness. The crude residue was purified by flash column chromatography on silica gel (19 mm×175 mm) using 50% ethyl acetate in hexanes to give N-tert-butyloxycarbonyl-sphingosine (540 mg, 90%) as a white solid.
^1H NMR (300MHz, chloroform-d) δ 5.77 (dt, J = 15.4, 8.4 Hz, 1H), 5.52 (dd, J = 15.4, 8.4 Hz, 1H), 3.93 (dd, J = 11.4, 3.7 Hz, 1H), 3.70 (dd, J = 11.4, 3.7 Hz, 1H), 3.59 (s, 3H), 2.05 (q, J = 7.0 Hz, 2H), 1.52 (s, 9H), 1.25 (s, 22H), 0.87 (t, J = 6.5 Hz, 3H).

[Example 46]
N-tert-Butyloxycarbonyl-sphingosine-1-O-dimethylphosphate (125)

N-tert-Butyloxycarbonyl-sphingosine 124 (540 mg, 1.35 mmol) was rendered dry by coevaporation with anhydrous pyridine (2×12 mL). The residue was then dissolved in anhydrous pyridine and treated with carbon tetrabromide (622 mg, 1.88 mmol). The mixture was cooled to 0° C. and treated dropwise with a solution of trimethylphosphite (0.25 mL, 2.10 mmol) in anhydrous pyridine (3 mL) over 30 min. After an additional 12 h at room temperature, both LCMS and tlc (5% methanol in methylene chloride) analysis indicated complete conversion. The mixture was quenched with water (2 mL) and then concentrated to dryness. The resulting dark oil was dissolved in ethyl acetate (150 mL) and washed with 3% HCl solution (2×20 mL) followed by saturated sodium bicarbonate solution (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (19 mm×175 mm) with 2% methanol in methylene chloride to afford N-tert-butyloxycarbonyl-sphingosine-1-O-dimethylphosphate 125 (350 mg, 51%) as a gum.
^1H NMR (400MHz, chloroform-d) δ 5.82 (dt, J = 15.4, 7.1 Hz, 1H), 5.48 (dd, J = 15.4, 7.1 Hz, 1H), 4.99 (d, J = 8.9 Hz, 1H), 4.32 (ddd, J = 10.7, 8.0, 4.6 Hz, 1H), 4.11 (ddt, J = 10.7, 7.4, 3.1 Hz, 2H), 3.77 (dd, J = 11.1, 2.1 Hz, 6H), 2.01 (q, J = 7.1 Hz, 2H), 1.41 (s, 9H), 1.34 (m, 2H), 1.23 (m, 20H), 0.86 (t, J = 6.4 Hz, 3H).
^31P NMR (162MHz, chloroform-d) δ 2.00.
MS C17H25NO4[M+Na+]; calculated: 330.2, found: 330.2.

[Example 47]
Sphingosine-1-phosphate (126)

A solution of N-tert-butyloxycarbonyl-sphingosine-1-O-dimethylphosphate 125 (350 mg, 0.689 mmol) in anhydrous methylene chloride (8 mL) was treated dropwise with trimethylsilyl bromide (0.45 mL, 3.45 mmol) at 0° C. After warming to room temperature, the mixture was stirred at room temperature for 6 h and then concentrated to dryness. The resulting residue was coevaporated with methylene chloride to remove excess trimethylsilyl bromide and then treated with 66% aqueous THF (6 mL). The resulting precipitate was collected by filtration to give sphingosine-1-phosphate 126 (218 mg, 83%) as a white solid.
^1H NMR (400MHz, methanol- _d4 + _CD3CO2D ) δ 5.84 (dt, J = 15.5, 6.7 Hz, 1H), 5.46 (dd, J = 15.5, 6.7 _Hz , 1H), 4.33 (t, J = 6.0 Hz, 1H), 4.13 (ddd, J = 11.8, 7.7, 3.6 Hz, 1H), 4.03 (dt, J = 11.8, 8.4 Hz, 1H), 3.47 (ddd, J = 8.3, 4.8, 3.2 Hz, 1H), 2.10-1.99 (m, 2H), 1.37 (m, 2H), 1.24 (m, 20H), 0.83 (t, J = 6.4 Hz, 3H).
^31P NMR (162MHz, chloroform-d) δ 0.69.
MS calculated _{for C18H38NO5P} [M-H ⁺ ]; _378.2 , found: 378.2.

[Example 48]
N-trifluoroacetyl-phytosphingosine (131)

To a slurry of phytosphingosine (4 g, 12.6 mmol) and anhydrous powdered potassium carbonate (5.22 g, 37.8 mmol) in methylene chloride (85 mL) was added trifluoroacetic anhydride (1.96 mL, 13.9 mmol). The mixture was stirred at room temperature for 18 h and then diluted with methylene chloride (500 mL). The mixture was washed with water (100 mL). Methanol (60 mL) was added to break the emulsion. The organic phase was then dried over sodium sulfate, filtered, and concentrated to give 131 (4.9 g, 94%) as a white solid.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 4.90-4.68 (m, 1H), 4.56 (d, J = 6.1 Hz, 1H), 4.43 (s, 1H), 3.97 (d, J = 7.6 Hz, 1H), 3.65 (d, J = 10.8 Hz, 1H), 3.46 (t, J = 10.2 Hz, 1H), 3.32-3.16 (m, 1H), 1.42 (tt, J = 15.7, 7.5 Hz, 2H), 1.20 (s, 24H), 0.83 t, J = 6.8 Hz, 3H.

[Example 49]
1-O-tert-butyldiphenylsilyl-2-N-trifluoroacetyl-phytosphingosine (132)

N-trifluoroacetyl-phytosphingosine (131, 1.88 g, 4.5 mmol) in anhydrous pyridine (23 mL) was treated with DMAP (56 mg, 0.45 mmol) followed by dropwise treatment with tert-butyldiphenylsilyl chloride (1.38 g, 5.0 mmol). After 18 h, it was concentrated to dryness. The resulting residue was dissolved in ethyl acetate (200 mL) and washed with saturated ammonium chloride (2×50 mL) followed by brine (50 mL). The aqueous phase was back-extracted with ethyl acetate (50 mL). The combined organic phase was dried over sodium sulfate and concentrated to give crude 1-O-tert-butyldiphenylsilyl-2-N-trifluoroacetyl-phytosphingosine 132 (3 g, 100%) as a gum. The material was used in the next step without further purification.
^1H NMR (400MHz, chloroform-d) δ 7.62 (m, 2H), 7.60-7.56 (m, 2H), 7.47-7.31 (m, 6H), 7.07 (d, J=8.4 Hz, 1H), 4.23 (dd, J=8.5, 4.1 Hz, 1H), 4.04 (dt, J=11.0, 2.5 Hz, 1H), 3.82 (ddd, J=11.0, 4.3, 1.8 Hz, 1H), 3.64 (dq, J=10.6, 6.0, 4.3 Hz, 2H), 1.45 (m, 2H), 1.39-1.15 (m, 24H), 1.05 (m, 9H), 0.94-0.80 (t, J=6.9 Hz 3H).

[Example 50]
1-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-2-N-trifluoroacetyl-phytosphingosine (133)

1-O-tert-Butyldiphenylsilyl-2-N-trifluoroacetyl-phytosphingosine. A solution of 132 (3 g, 4.5 mmol) in 1/1 (v/v) 2,2-dimethoxypropane/THF was treated with a catalytic amount of p-toluenesulfonic acid (87 mg, 0.45 mmol) and stirred at room temperature for 16 h. The mixture was quenched with saturated sodium bicarbonate (30 mL) and then the excess THF/2,2-dimethoxypropane was removed under vacuum. The mixture was extracted with ethyl acetate (200 mL). After washing with brine, the organic layer was dried over sodium sulfate, filtered and concentrated. The crude oil was purified by column chromatography on silica gel (25 mm×175 mm) using a mobile phase of hexane/ethyl acetate to give 133 (2.45 g, 78%).
¹ H NMR (400 MHz, chloroform-d) δ 7.68-7.63 (m, 2H), 7.63-7.57 (m, 2H), 7.39 (m, 6H), 6.54 (d, J = 9.4 Hz, 1H), 4.23 (dd, J = 8.2, 5.6 Hz, 1H), 4.12 (ddd, J = 13.3, 6.9, 3.8 Hz, 2H), 3.96 (dd, J = 10.5, 3.9 Hz, 1H), 3.69 (dd, J = 10.5, 2.9 Hz, 1H), 1.52-1.36 (m, 2H), 1.33 (s, 3H), 1.31 (s, 3H), 1.24 (m, 24H), 1.03 (s, 9H), 0.86 (t, J = 53.7, 6.9 Hz, 3H).

[Example 51]
3,4-O-isopropylidene-2-N-trifluoroacetyl-phytosphingosine (134)

A solution of 1-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-2-N-trifluoroacetyl-phytosphingosine 133 (2.45 g, 3.54 mmol) in THF (18 mL) was treated with tetrabutylammonium fluoride (4.25 mL of a 1.0 M solution in THF, 4.25 mmol) and stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (100 mL) and saturated ammonium chloride (2×50 mL) and then with brine (50 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated to give a white solid which was further purified by column chromatography on silica gel (25 mm×175 mm) using a mobile phase of 9:1 hexanes:ethyl acetate to give 134 (1.5 g, 93%) as a white solid.
^1H NMR (300MHz, chloroform-d) δ 6.92 (d, J = 8.7 Hz, 1H), 4.31-4.16 (m, 2H), 4.11 (dq, J = 11.7, 3.7 Hz, 1H), 4.00 (dd, J = 11.5, 2.6 Hz, 1H), 3.70 (dd, J = 11.5, 3.6 Hz, 1H), 1.48 (s, 3H), 1.35 (s, 3H), 1.25 (m, 26H), 0.88 (t, J = 6.9 Hz 3H).

[Example 52]
3,4-O-isopropylidene-2-N-trifluoroacetyl-phytosphingosine-1-O-dimethyl phosphate (135)

A solution of 3,4-O-isopropylidene-2-N-trifluoroacetyl-phytosphingosine 134 (630 mg, 1.39 mmol) was rendered dry by coevaporation with anhydrous pyridine (2×12 mL). The residue was then dissolved in anhydrous pyridine (12 mL) and treated with carbon tetrabromide (533 mg, 1.67 mmol). The mixture was cooled to 0° C. and treated dropwise with a solution of trimethylphosphite (0.23 mL, 1.95 mmol) in anhydrous pyridine (3 mL) over 30 min. After a further 12 h at room temperature, both LCMS and tlc (5% methanol in methylene chloride) analysis indicated complete conversion. The mixture was quenched with water (2 mL) and then concentrated to dryness. The resulting dark oil was dissolved in ethyl acetate (100 mL) and washed with 3% HCl solution (2×20 mL) followed by saturated sodium bicarbonate solution (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (19 mm×175 mm) with 2% methanol in methylene chloride to give 135 (650 mg, 83%).
^1H NMR (300 MHz, chloroform-d) δ 7.42 (d, J = 8.8 Hz, 1H), 4.36 (td, J = 10.9, 5.0 Hz, 1H), 4.25 (m, 1H), 4.19 (m, J = 6.5, 2.0 Hz, 3H), 3.77 (dd, J = 11.2, 7.5 Hz, 6H), 1.44 (s, 3H), 1.33 (s, 3H), 1.25 (m, 26H), 0.87 (t, J = 6.6 Hz, 3H).
^31P NMR (121MHz, chloroform-d) δ 1.69.
MS calculated _{for C25H47F3NO7P [} M _- H ⁺ ]: _560.3 , found: 560.2.

[Example 53]
3,4-O-isopropylidene-2-N-trifluoroacetyl-phytosphingosine-1-phosphate (136)

3,4-O-Isopropylidene-2-N-trifluoroacetyl-phytosphingosine-1-O-dimethylphosphate. A solution of 135 (650 mg, 1.16 mmol) in anhydrous methylene chloride (12 mL) was treated dropwise with trimethylsilyl bromide (0.81 mL, 6.23 mmol) at 0° C. After 12 h at room temperature, the mixture was concentrated to dryness and the resulting residue was coevaporated with methylene chloride (3×50 mL) to remove excess trimethylsilyl bromide. The residue was then dissolved in a cold (4° C.) solution of 1% NH ₄ OH while maintaining the pH at 7-8. After 10 min at room temperature, the mixture was concentrated to dryness and the resulting solid was triturated with methanol/acetonitrile. The solid was collected by filtration, washed with acetonitrile, and dried under high vacuum to give 136 (500 mg, 75%) as a white solid.
¹ H NMR (300 MHz, methanol-d ₄ ) δ 4.31 (dd, J=8.7, 5.4 Hz, 1H), 4.09 (m, 4H), 1.42 (s, 3H), 1.36 (s, 3H), 1.31 (m, 26H), 0.89 (t, J=6.4 Hz, 3H).
³¹ P NMR (121 MHz, methanol-d ₄ ) δ 1.28.
¹⁹ F NMR (282 MHz, methanol-d ₄ ) δ-77.13.
HRMS _C23H42F3NO7P [M _- H ⁺ ]; calculated: _{532.26565 ,} found: 532.26630.

[Example 54]
2',3'-dideoxy-2'-fluoro-5'-(N-trifluoroacetyl-3,4-O-isopropylidene-phytosphingosine-1-phospho)-7-deazaguanosine (137)

A mixture of N-trifluoroacetyl-phytosphingosine-1-phosphate 136 (200 mg, 0.373 mmol) and 2',3'-dideoxy-2'-fluoro-7-deazaguanine (100 mg, 0.373 mmol) was rendered dry by coevaporation with anhydrous pyridine (3 x 10 mL). The resulting residue was then dissolved in anhydrous pyridine (4 mL) and treated with diisopropylcarbodiimide (127 mg, 1.01 mmol) and HOBt (60 mg, 0.447 mmol). After 24 h at 75°C, the reaction mixture was cooled to room temperature and concentrated to dryness. The crude material was purified by flash column chromatography on silica gel (19 mm x 170 mm) using a solvent gradient of 5 to 7.5% methanol in chloroform with 1% (v/v) NH ₄ OH to give 137 (80 mg, 27%) as a white solid.
¹ H NMR (300 MHz, methanol-d ₄ ) δ 6.88 (d, J = 3.8 Hz, 1H), 6.46 (d, J = 3.8 Hz, 1H), 6.24 (d, J = 19.9 Hz, 1H), 5.34 (dd, J = 52.4, 4.6 Hz, 1H), 4.53 (s, 1H), 4.34-3.97 (m, 6H), 2.63-2.17 (m, 2H), 1.40 (s, 3H), 1.30 (s, 3H), 1.27 (m, 26H), 0.89 (t, J = 6.6 Hz, 3H).
³¹ P NMR (121 MHz, methanol-d ₄ ) δ 12.50.
¹⁹ F NMR (282 MHz, methanol-d ₄ ) δ-77.10, -179.69--180.25 (m).
MS _{calculated for C34H522F4N5O9P} [ _M -H ⁺ ]: _781.3 , found: 782.2.

[Example 55]
Experimental procedure for the synthesis of the prodrug. A solution of isopropyl 2-((chloro(phenoxy)phosphoryl)amino)propanoate (0.397 g, 1.300 mmol) in anhydrous THF (5 ml) was added to a stirred solution of 2'-deoxy-2'-fluoronucleoside (0.812 mmol) and 1-methyl-1H-imidazole (0.367 ml, 4.63 mmol) in pyridine (10.00 ml) at -78°C. After 15 min the reaction was allowed to warm to room temperature and stirred for an additional 3 h. The solvent was then removed under reduced pressure. The crude product was dissolved in 120 ml DCM and washed with 20 ml of 1N HCl solution followed by 10 ml of water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was separated on a silica column (neutralized with TEA) using 5% MeOH in DCM as the mobile phase to give the respective products as diastereomers.

[Example 56]

^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ １．４８－１．０６（ｍ，９Ｈ）、４．０４－３．８４（ｍ，１Ｈ）、４．６０－４．１４（ｍ，３Ｈ）、４．８６－４．６４（ｍ，１Ｈ）、５．１１－４．９０（ｍ，１Ｈ）、５．６１－５．１９（ｍ，１Ｈ）、６．３２－５．９４（ｍ，３Ｈ）、７．４４－７．０２（ｍ，５Ｈ）、８．１１－７．８９（ｍ，１Ｈ）、８．４６－８．２０（ｍ，１Ｈ）。ＬＣ－ＭＳ ｍ／ｚ ５８９．４（Ｍ＋Ｈ^＋）。

^1H NMR (400MHz, _CDCl3 ) δ 1.48-1.06 (m, 9H), 4.04-3.84 (m, 1H), 4.60-4.14 (m, 3H), 4 . 86-4.64 (m, 1H), 5.11-4.90 (m, 1H), 5.61-5.19 (m, 1H), 6.32-5.94 (m, 3H) , 7.44-7.02 (m, 5H), 8.11-7.89 (m, 1H), 8.46-8.20 (m, 1H). LC-MS m/z 589.4 (M+H ⁺ ).

[Example 57]

^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ １．１４－１．２９（ｍ，６Ｈ）、１．３１－１．４３（ｍ，３Ｈ）、３．８３－４．０７（ｍ，２Ｈ）、４．１５－４．５４（ｍ，３Ｈ）、４．９１－５．１１（ｍ，１Ｈ）、５．６１－５．７４（ｍ，１Ｈ）、５．８１－５．９７（ｍ，１Ｈ）、７．１４－７．２４（ｍ，３Ｈ）、７．２７－７．４４（ｍ，２Ｈ）、７．４８－７．５１（ｍ，１Ｈ）、７．８０（ｔ，Ｊ＝７．９６，７．９６Ｈｚ，ＯＨ）、９．３０（ｓ，１Ｈ）。ＬＣ－ＭＳ ｍ／ｚ ５１６．３（Ｍ＋１^＋）

^1H NMR (400MHz, _CDCl3 ) δ 1.14-1.29 (m, 6H), 1.31-1.43 (m, 3H), 3.83-4.07 (m, 2H), 4 . 15-4.54 (m, 3H), 4.91-5.11 (m, 1H), 5.61-5.74 (m, 1H), 5.81-5.97 (m, 1H) , 7.14-7.24 (m, 3H), 7.27-7.44 (m, 2H), 7.48-7.51 (m, 1H), 7.80 (t, J = 7. 96, 7.96Hz, OH), 9.30 (s, 1H). LC-MS m/z 516.3 (M+1 ⁺ )

[Example 58]
Phosphonate Synthesis

試薬および条件：ａ）ＢＡＩＢ、ＴＥＭＰＯ；ｂ）Ｐｂ（ＯＡｃ）_４；ｃ）（ＥｔＯ）_２ＰＯＣＨ_２ＯＨ、ｐＴＳＡ

Reagents and conditions: a) BAIB, TEMPO; b) Pb(OAc) ₄ ; c) (EtO) _2POCH2OH , pTSA _.

[Example 59]

試薬および条件：ａ）ｉ．Ｐｔ／Ｃ、Ｏ_２、ｉｉ．ＤＭＦ－ジネオペンチルアセタール；ｂ）ＩＢｒ、（ＥｔＯ）_２ＰＯＣＨ_２ＯＨ；ｃ）ＡＩＢＮ、Ｂｕ_３ＳｎＨ；ｄ）ｉ．ＡｇＯＡｃ、ｉｉ．ＮａＯＭｅ、ＭｅＯＨ、ｉｉｉ．ＰＰｈ_３、ＤＩＡＤ、４－ＮＯ_２Ｃ_６Ｈ_４ＣＯＯＨ、ｉｖ．ＮａＯＭｅ、ＭｅＯＨ。

Reagents and conditions: a) i. Pt/C, O ₂ , ii. DMF-dineopentyl acetal; b) IBr, (EtO) ₂ POCH ₂ OH; c) AIBN, Bu ₃ SnH; d) i. AgOAc, ii. NaOMe, MeOH, iii. PPh ₃ , DIAD, 4-NO ₂ C ₆ H ₄ COOH, iv. NaOMe, MeOH.

[Example 60]

試薬および条件：ａ）ｉ．Ｉ_２、アセトン、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｂ）Ｐｔ／Ｃ、Ｏ_２；ｃ）ｉ．Ｐｂ（ＯＡｃ）_４、ｉｉ．Ａｃ_２Ｏ、ＤＭＡＰ；ｄ）ｉ．（ＥｔＯ）_２ＰＯＣＨ_２ＯＨ、ｐＴＳＡ、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｅ）ＢｎＣｌ、ＫＯＨ；ｆ）Ａｃ_２Ｏ、ＡｃＯＨ、Ｈ_２ＳＯ_４；ｇ）ｉ．シリル化塩基、ＴＭＳＯＴｆ、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｈ）ＤＭＰ；ｉ）ｉ．ＲＬｉまたはＲＭｇＢｒ、ｉｉ．ＤＡＳＴ；ｊ）Ｈ_２、Ｐｄ／Ｃ。

Reagents and conditions: a) i. _I2 , acetone, _ii . _K2CO3 , MeOH; b) Pt/C, _O2 ; c ₎ i. Pb(OAc) ₄ , ii. _Ac2O , DMAP; d) i. (EtO) _{2POCH2OH ,} pTSA, _ii . K2CO3, MeOH; e) BnCl, KOH; f) _Ac2O , AcOH, _{H2SO4 ;} g) i. silylated base, TMSOTf, _ii . _K2CO3 , MeOH; h) DMP; i) i. RLi or RMgBr, ii. DAST; j) _H2 , Pd/C.

[Example 61]

試薬および条件：ａ）ｉ．Ｉ_２、アセトン、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｂ）Ｐｔ／Ｃ、Ｏ_２；ｃ）ｉ．Ｐｂ（ＯＡｃ）_４、ｉｉ．Ａｃ_２Ｏ、ＤＭＡＰ；ｄ）ｉ．（ＥｔＯ）_２ＰＯＣＨ_２ＯＨ、ｐＴＳＡ、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｅ）ｉ．ＴＣＤＩ、ピリジン、ｉｉ．Ｂｕ_３ＳｎＨ、ＡＩＢＮ；ｆ）Ａｃ_２Ｏ、ＡｃＯＨ、Ｈ_２ＳＯ_４；ｇ）ｉ．シリル化塩基、ＴＭＳＯＴｆ、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ；ｈ）ＤＭＰ；ｉ）ｉ．ＲＬｉまたはＲＭｇＢｒ、ｉｉ．ＤＡＳＴ

Reagents and conditions: a) i. _I2 , acetone, _ii . _K2CO3 , MeOH; b) Pt/C, _O2 ; c ₎ i. Pb(OAc) ₄ , ii _{. Ac2O} , DMAP; d) i. (EtO)2POCH2OH, pTSA, ii _. K2CO3, MeOH; e ₎ i. TCDI, pyridine, ii. Bu3SnH, AIBN; f) _Ac2O , AcOH _{, H2SO4} ; g) i. silylated base, _TMSOTf , ii. _{K2CO3 ,} MeOH; h) DMP; i) i. RLi or RMgBr, ii. DAST.

[Example 62]

試薬および条件：ａ）ｉ．ＳＯＣｌ_２、ｉｉ．ＮａＩＯ_４、ＲｕＣｌ_３；ｂ）ＴＢＡＦ；ｃ）ＢＦ_３・ＯＥｔ_２、ＤＩＢＡＬ；ｄ）Ａｃ_２Ｏ、ＡｃＯＨ、Ｈ_２ＳＯ_４；ｅ）（ＥｔＯ）_２ＰＯＣＨ_２ＯＨ、ｐＴＳＡ；ｆ）ｉ．ＤＩＢＡＬ、ｉｉ．Ａｃ_２Ｏ、Ｅｔ_３Ｎ、ＤＭＡＰ；ｇ）ｉ．シリル化塩基、ＴＭＳＯＴｆ、ｉｉ．Ｋ_２ＣＯ_３、ＭｅＯＨ

Reagents and conditions: a) _{i. SOCl2} , ii. _NaIO4 , _RuCl3 ; b) TBAF; c) _{BF3.OEt2 ,} DIBAL; d) _Ac2O , AcOH, _H2SO4 ; e) (EtO) _2POCH2OH , pTSA; f) i. DIBAL, ii _{. Ac2O} , _Et3N , DMAP; g) i. silylated base, TMSOTf, _ii . _K2CO3 , MeOH _.

[Example 63]
Phosphonate Prodrug Synthesis

試薬および条件：ａ）ＴＭＳＢｒ；ｂ）アミノエステル、ＡｒＯＨ、Ｅｔ_３Ｎ、２，２’－ジチオジピリジン、ＰＰｈ_３；ｃ）ｉ．ＤＩＣ、スフィンゴイド塩基、ｉｉ．ＴＦＡ；ｄ）クロロホスホルアミデート、Ｅｔ_３Ｎ；ｅ）ＤＩＣ、スフィンゴイド塩基－１－リン酸

Reagents and conditions: a) TMSBr; b) amino ester, ArOH, Et ₃ N, 2,2'-dithiodipyridine, PPh ₃ ; c) i. DIC, sphingoid base, ii. TFA; d) chlorophosphoramidate, Et ₃ N; e) DIC, sphingoid base-1-phosphate.

[Example 64]
N-tert-Butyloxycarbonyl-Phytosphingosine (174)

A suspension of phytosphingosine (10.6 g, 33.5 mmol) and triethylamine (5.6 ml, 40.2 mmol) in THF (250 mL) was treated dropwise with di-tert-butyl dicarbonate (8.6 mL, 36.9 mmol). After 12 h at room temperature, the mixture was concentrated to dryness and the resulting white solid was recrystallized from ethyl acetate (80 mL) and then dried under high vacuum at 35° C. for 12 h to give 174 (10.5 g, 75%).
^1H NMR (400MHz, chloroform-d) δ 5.31 (d, J = 8.5 Hz, 1H), 3.89 (d, J = 11.1 Hz, 1H), 3.83 (s, 2H), 3.74 (dd, J = 11.1, 5.2 Hz, 1H), 3.65 (d, J = 8.3 Hz, 1H), 3.61 (d, J = 3.9 Hz, 1H), 1.43 (s, 9H), 1.23 (s, 27H), 0.86 (t, J = 6.4 Hz, 3H).

[Example 65]
2-O-tert-butyldiphenylsilyl-1-N-tert-butyloxycarbonyl-phytosphingosine (175)

A solution of N-tert-butyloxycarbonyl-phytosphingosine 174 (9.5 g, 22.65 mmol) and triethylamine (3.8 mL, 27.2 mmol) in anhydrous methylene chloride/DMF (120 mL/10 mL) was treated dropwise with tert-butylchlorodiphenylsilane (7 mL, 27.25 mmol). After 18 h at room temperature, the mixture was diluted with methylene chloride (200 mL) and washed with 0.2 N HCl (100 mL) followed by brine (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to give 175 (14.9 g) as an oil which was used in the next reaction without further purification.
^1H NMR (400MHz, chloroform-d) δ 5.31 (d, J = 8.5 Hz, 1H), 3.89 (d, J = 11.1 Hz, 1H), 3.83 (m, 1H), 3.74 (dd, J = 11.1, 5.2 Hz, 1H), 3.65 (d, J = 8.3 Hz, 1H), 3.61 (d, J = 3.9 Hz, 1H), 1.43 (s, 9H), 1.23 (s, 27H), 0.86 (t, J = 6.4 Hz, 3H).

[Example 66]
2-O-tert-butyldiphenylsilyl-1-N-tert-butyloxycarbonyl-3,4-O-isopropylidene-phytosphingosine (176)

A solution of 2-O-tert-butyldiphenylsilyl-1-N-tert-butyloxycarbonyl-phytosphingosine (175, 14.9 g, 22.65 mmol) in 1/1 (v/v) THF/2,2-dimethoxypropane was treated with catalytic paratoluenesulfonic acid (860 mg, 4.53 mmol). After 24 h, the mixture was quenched with saturated sodium bicarbonate solution (50 mL). The mixture was concentrated and then dissolved in ethyl acetate (200 mL) and washed with brine (2×50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to give 176 (15.7 g) as a gum which was used in the next step without further purification.
^1H NMR (400MHz, chloroform-d) δ 7.66 (m, 4H), 7.51-7.27 (m, 6H), 4.78 (d, J = 10.0 Hz, 1H), 4.18 (dd, J = 9.3, 5.5 Hz, 1H), 3.89 (dd, J = 9.9, 3.3 Hz, 1H), 3.80 (d, J = 9.9 Hz, 1H), 3.72 (d, J = 9.9 Hz, 1H), 1.45 (s, 9H), 1.42 (s, 3H), 1.35 (s, 3H), 1.25 (s, 27H), 1.05 (s, 9H), 0.87 (t, J = 6.5 Hz, 3H).

[Example 67]
1-N-tert-Butyloxycarbonyl-3,4-O-isopropylidene-phytosphingosine (177)

A solution of 2-O-tert-butyldiphenylsilyl-1-N-tert-butyloxycarbonyl-3,4-O-isopropylidene-phytosphingosine 176 (15.7 g, 22.6 mmol) in THF at 0° C. was treated dropwise over 20 min with a solution of tetrabutylammonium fluoride (1.0 M in THF, 24.9 mL, 24.9 mmol). After 16 h at room temperature, tlc (3:1 hexanes:ethyl acetate) indicated complete conversion. The mixture was concentrated to dryness and the resulting residue was dissolved in ethyl acetate (300 mL) and washed with water (3×100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated. The resulting oil was purified by flash column chromatography (35 mm×180 mm) using a solvent gradient of 25 to 50% ethyl acetate in hexanes to give 177 (7.3 g, 71% over three steps) as a white solid.
^1H NMR (400MHz, chloroform-d) δ 4.93 (d, J=9.1, 1H), 4.16 (q, J=7.1, 6.4Hz, 1H), 4.07 (t, J=6.5Hz, 1H), 3.83 (dd, J=11.1, 2.4Hz, 1H), 3.76 (m, 1H), 3.67 (dd, J=11.2, 3.6Hz, 1H), 1.43 (s, 3H), 1.42 (s, 9H), 1.32 (s, 3H), 1.23 (s, 27H), 0.86 (t, J=6.9Hz, 3H).

[Example 68]
Synthesis of Cyclic Phosphate Prodrugs

試薬および条件：ａ）ｉ．Ｒ_１ＯＰ（ＮｉＰｒ_２）_２、ＤＣＩ、ｉｉ．ｍＣＰＢＡ；ｂ）ｉ．クロロホスホルアミデート、イミダゾール、ｉｉ．ｔ－ＢｕＯＫ；ｃ）ｉ．イミダゾール、ｉｉ．ｔ－ＢｕＯＫ

Reagents and conditions: a) i. R ₁ OP(NiPr ₂ ) ₂ , DCI, ii. mCPBA; b) i. chlorophosphoramidate, imidazole, ii. t-BuOK; c) i. imidazole, ii. t-BuOK.

[Example 69]
General Method for the Synthesis of 4-Thiouridine Nucleoside Analogues

試薬および条件：ａ）Ａｃ_２Ｏ、Ｅｔ_３Ｎ、ＤＭＡＰ；ｂ）ローソン試薬、ジオキサン、還流；ｃ）ＮＨ_３、ＭｅＯＨ

Reagents and conditions: a) _Ac2O , _Et3N , DMAP; b) Lawesson's reagent, dioxane, reflux; c) _NH3 , MeOH.

[Example 70]

A suspension of 2'-methyluridine (0.258 g, 0.999 mmol) in Ac ₂ O (4.00 ml) was stirred overnight at room temperature in the presence of DMAP (0.024 g, 0.200 mmol) and Et ₃ N (0.139 ml, 0.999 mmol). The reaction mixture became homogeneous and yellowish upon stirring. The reaction was concentrated on a rotavap and coevaporated with EtOH (15 mL x 3). The product was purified by ISCO to give a white solid in >95% yield.
Physical data: ^1H NMR (400Hz, _CDCl3 ): δ 1.519 (s, 3H), 2.087 (s, 6H), 2.099 (s, 3H), 4.265 (m, 1), 4.369 (m, 2H), 5.220 (d, 1H, J = 6Hz), 5.756 (d, 1H, J = 8Hz), 6.217 (s, 1H), 7.407 (d, 1H, J = 8Hz), 9.744 (s, 1H); ^13C NMR (100Hz, _CDCl3 ): δ 17.773, 20.520, 20.687, 21.461, 62.649, 74.313, 79.284, 84.195, 89.409, 102.364, 140.530, 150.040, 163.071, 169.643, _169.742 , 170.318; MS: m/ _{z 273.1} (M-uracil+H); LC-MS purity 99.6%; HRMS calculated for _C16H21O9N2 (M+H): 385.12416, found: 385.12420.

[Example 71]

A mixture of per-Ac-2'-methyluridine (0.100 g, 0.260 mmol) and Lawesson's reagent (0.127 g, 0.315 mmol) in dry dioxane (1.301 ml) was refluxed under nitrogen for 2 h. The reaction was condensed on a rotavap and the resulting yellow residue was loaded onto an ISCO and eluted with 3% MeOH/CH ₂ Cl _2. The resulting yellow foam was used in the next step without further purification and LC-MS showed 53% purity.

[Example 72]

A solution of crude per-Ac-5-thio-2'-methyluridine from the previous step (0.126 g, 0.315 _mmol ) in NH in MeOH ( ₇ M, 1.573 ml, 11.01 mmol) was stirred at room temperature in a sealed tube for 4.5 h. The yellow solution was condensed on the rotavap and loaded onto the ISCO (4 g column, 8% -> 15% MeOH/ _CH2Cl2 ) to give a yellow foam in 55% yield over two steps.
Physical data: ¹ H NMR (400 Hz, CD ₃ OD): δ 1.201 (s, 3H), 3.835 (m, 2H), 3.983 (m, 2H), 5.595 (s, 1H), 6.396 (d, 1H, J=7.6 Hz), 8.006 (d, 1H, J=7.2 Hz); ¹³ C NMR (100 Hz, CD ₃ OD): δ 20.983, 61.259, 74.123, 80.862, 84.809, 94.144, 114.863, 137.236, 150.806, 192.972; MS: m/z 275.0 (M+H); LC-MS purity 95.9%; HRMS C ₁₀ H Calculated _{for 15O5N2S (} M+H): _275.06962 , found: 275.06967.

[Example 73]

試薬および条件：ａ）Ａｃ_２Ｏ、Ｅｔ_３Ｎ、ＤＭＡＰ；ｂ）ローソン試薬、ジオキサン、還流；ｃ）ＮＨ_３、ＭｅＯＨ

Reagents and conditions: a) _Ac2O , _Et3N , DMAP; b) Lawesson's reagent, dioxane, reflux; c) _NH3 , MeOH.

[Example 74]

A brownish suspension of 2'-F-2'-methyluracil (0.120 g, 0.461 mmol) in Ac ₂ O (1.845 ml) was stirred in the presence of DMAP (5.63 mg, 0.046 mmol) at room temperature for 2 h. The reaction mixture became homogeneous upon stirring. The reaction was concentrated on a rotavap and coevaporated with MeOH (5 mL x 2). The resulting residue was purified by ISCO (12 g column, 40% -> 80% EtOAc/Hexanes) to give a white solid in 81% yield.
Physical data: ^1H NMR (400Hz, _CDCl3 ): δ 1.398 (d, 3H, J = 22Hz), 2.142 (s, 3H), 2.183 (s, 3H), 4.379 (m, 3H), 5.128 (dd, 1H, J, = 21.2Hz, _J2 = 8.8Hz), 5.788 (d, 1H, J = 8.4Hz), 6.179 (d, 1H, J = 18.4Hz), 7.549 (d, 1H, J = 8Hz), 8.882 (s 1H); ^13C NMR (100Hz, _CDCl3 ): δ 17.113, 17.363, 20.490, 20.672, 61.457, 71.498, 71.665, 98.539, 100.390, 103.085, 138.990, 149.911, 162.312, 169.924; MS: _m / _{z 345.0} (M-uracil+H); LC-MS purity 95%; HRMS calculated for _C14H18FO7N2 (M+H): 345.10926, found: 345.10906.

[Example 75]

A yellow suspension of per-Ac-2'-F-2'-methyluracil (0.129 g, 0.375 mmol) and Lawesson's reagent (0.183 g, 0.453 mmol) in dry dioxane (1.873 ml) was refluxed under argon for 1 h, and the yellow suspension became homogeneous upon heating. The reaction was condensed on a rotavap and the yellow residue was loaded onto an ISCO (12 g column, 20%→100% EtOAc/Hexanes). The resulting yellow foam showed 74% purity of the desired product by LC-MS and was used in the next step without further purification.

[Example 76]

A solution of per-Ac-2'-F-2'-methyl-4-thiouracil (0.135 g, 0.375 mmol) in _NH3 in MeOH (7 M, 1.873 ml, 13.11 mmol) was stirred in a sealed tube at room temperature for 4.5 h ( _10:04:05 AM). The yellow solution was condensed on the rotavap and loaded onto an ISCO (4 g column, 5% -> 12% MeOH/ _CH2Cl2 ). The product was a yellow foam in 73% yield over two steps.
Physical data: ^1H NMR (400Hz, _CD3OD ): δ 1.367 (d, 3H, J = 22.4Hz), 3.794 (dd, 1H, _J1 = 12.4Hz, _J2 = 2.4Hz), 3.971 (m, 3H), 6.094 (d, 1H, J = 18Hz), 6.368 (d, 1H, J = 7.6Hz), 7.888 (d, 1H, J = 7.6Hz). ^13C NMR (100 Hz, CD3OD): δ 16.757 (d,J=25 Hz), 59.951 _, 72.276, 83.395, 90.704 (d,J=34.9 Hz), 101.894 (d,J=179.9 Hz), 114.435, 135.602, 149.733, _192.200 ; MS: m/ _{z 277.0} (M+H); LC-MS purity 100%; HRMS calculated for _C10H14FO4N2S (M+H): 277.06528, found: 277.06496.

[Example 77]

試薬および条件：ａ）ジオキサン、ローソン試薬、還流；ｂ）ＮＨ_３／ＭｅＯＨ

Reagents and conditions: a) dioxane, Lawesson's reagent, reflux; b) _NH3 /MeOH

[Example 78]

A stirred solution of benzoate (1 g, 1.37 mmol) in dioxane (6.9 mL, 0.2 M) was charged with Lawesson's reagent (673 mg, 1.66 mmol) and heated to reflux, during which the reaction became homogeneous and brown. After 2 h, the reaction was concentrated and purified by silica gel chromatography (10-30% ethyl acetate in hexanes) to give 600 mg of thiouridine, 68%.

[Example 79]

A stirred solution of benzoate (600 mg, 2.08 mmol) in ammonia (9 mL, 7 M in methanol) was prepared. After 16 h, the reaction was concentrated and purified by silica gel chromatography (2-15% methanol in dcm) to give 269 mg of thiouridine, 87%.

[Example 80]

試薬および条件：ａ）ジオキサン、ローソン試薬、還流；ｂ）ＴＢＡＦ、ＴＨＦ

Reagents and conditions: a) dioxane, Lawesson's reagent, reflux; b) TBAF, THF.

[Example 81]

1-((6aR,8R,9S,9aR)-2,2,4,4-tetraisopropyl-9-methyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilosin-8-yl)pyrimidine-2,4(1H,3H)-dione (0.16 g, 0.33 mmol) was heated with Lawesson's reagent (0.17 g, 0.43 mmol) in dry 1,4-dioxane (1.65 mL) under argon for 1 h. The solvent was then removed in vacuo and the crude material was purified by ISCO column chromatography eluting with 10% to 40% EtOAc in hexanes to give 1-((6aR,8R,9S,9aR)-2,2,4,4-tetraisopropyl-9-methyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilosin-8-yl)-4-thioxo-3,4-dihydropyrimidin-2(1H)-one (0.11 g, 67%) as a yellow solid.
^1H NMR (400MHz, _CDCl3 ) δ 9.33 (bs, 1H), 7.68 (d, J = 7.6 Hz, 1H), 6.40 (dd, J = 7.6, 1.6 Hz), 6.20 (d, J = 7.2 Hz, 1H), 4.18 (d, J = 13.6 Hz, 1H), 4.04-3.89 (m, 2H), 3.78 (dd, J = 8.8, 2.4 Hz, 1H), 2.71-2.62 (m, 1H), 1.12-0.84 (m, 31H).

[Example 82]

1-((6aR,8R,9S,9aR)-2,2,4,4-tetraisopropyl-9-methyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilosin-8-yl)-4-thioxo-3,4-dihydropyrimidin-2(1H)-one (0.11 g, 0.22 mmol) was stirred with TBAF (1.0 M in THF, 0.44 mL, 0.44 mmol) at room temperature overnight. The solvent was then removed in vacuo and the crude material was purified by SiO ₂ column chromatography eluting with 100% DCM to 4% MeOH in DCM to afford 1-((2R,3S,4R,5R)-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-4-thioxo-3,4-dihydropyrimidin-2(1H)-one (33 mg, 58%) as a yellow solid.
^1H NMR (400MHz, _CD3OD ) δ 7.81 (d, J=7.6Hz 1H), 6.38 (d, J=8.0Hz, 1H), 6.17 (d, J=7.6Hz, 1H), 3.96-3.71 (m, 4H), 2.53-2.50 (m, 1H), 0.96 (d, J=7.2Hz, 3H).
LCMS _C10H13N2O4S [ _{M +} H ⁺ ]; calculated: _257.1 , found 256.9.

[Example 83]
Synthetic Routes for the Synthesis of 2'-Fluoro-2-Thiouridine Nucleoside Analogues

試薬および条件：ａ）塩化トシル、Ｅｔ_３Ｎ、ＤＭＡＰ；ｂ）ＮａＨＣＯ_３、エタノール、還流；ｃ）ＮａＳＨ、ＤＭＦ
２’－フルオロ－２－チオウリジンヌクレオシド類似体は、親ヌクレオシド（１当量）を、不活性雰囲気下、ピリジン：ＤＣＭ（１：１）に溶解した塩化トシル（１．２当量）で処理することにより作製することができる。次いで、得られた５’－トシルヌクレオシド類似体を還流エタノール中重炭酸ナトリウム（５当量）で処理して、２－エトキシヌクレオシドを得ることができる。最後に、所望の２－チオヌクレオシド類似体は、２－エトキシ中間体をＤＭＦなどの極性溶媒中の水硫化ナトリウム（１０当量）で処理することにより得ることができる。

Reagents and conditions: a) tosyl chloride, Et ₃ N, DMAP; b) NaHCO ₃ , ethanol, reflux; c) NaSH, DMF
The 2'-fluoro-2-thiouridine nucleoside analogs can be made by treating the parent nucleoside (1 equivalent) with tosyl chloride (1.2 equivalents) dissolved in pyridine:DCM (1:1) under an inert atmosphere. The resulting 5'-tosyl nucleoside analog can then be treated with sodium bicarbonate (5 equivalents) in refluxing ethanol to give the 2-ethoxy nucleoside. Finally, the desired 2-thio nucleoside analogs can be obtained by treating the 2-ethoxy intermediate with sodium hydrosulfide (10 equivalents) in a polar solvent such as DMF.

[Example 84]
Synthetic Routes for the Synthesis of 2'-Fluoro-2'-Methyl-2-Thiouridine Nucleoside Analogues

試薬および条件：ａ）塩化トシル、Ｅｔ_３Ｎ、ＤＭＡＰ；ｂ）ＮａＨＣＯ_３、エタノール、還流；ｃ）ＮａＳＨ、ＤＭＦ
２’－フルオロ－２’－メチル－２－チオウリジンヌクレオシド類似体は、親ヌクレオシド（１当量）を、不活性雰囲気下、ピリジン：ＤＣＭ（１：１）に溶解した塩化トシル（１．２当量）で処理することにより作製することができる。次いで、得られた５’－トシルヌクレオシド類似体を還流エタノール中重炭酸ナトリウム（５当量）で処理して、２－エトキシヌクレオシドを得ることができる。最後に、所望の２－チオヌクレオシド類似体は、２－エトキシ中間体をＤＭＦなどの極性溶媒中の水硫化ナトリウム（１０当量）で処理することにより得ることができる。

Reagents and conditions: a) tosyl chloride, Et ₃ N, DMAP; b) NaHCO ₃ , ethanol, reflux; c) NaSH, DMF
The 2'-fluoro-2'-methyl-2-thiouridine nucleoside analogs can be made by treating the parent nucleoside (1 equivalent) with tosyl chloride (1.2 equivalents) dissolved in pyridine:DCM (1:1) under an inert atmosphere. The resulting 5'-tosyl nucleoside analog can then be treated with sodium bicarbonate (5 equivalents) in refluxing ethanol to give the 2-ethoxy nucleoside. Finally, the desired 2-thio nucleoside analogs can be obtained by treating the 2-ethoxy intermediate with sodium hydrosulfide (10 equivalents) in a polar solvent such as DMF.

[Example 85]
Synthetic Routes for the Synthesis of 2'-C-Methyl-2-Thiouridine Nucleoside Analogues

試薬および条件：ａ）塩化トシル、Ｅｔ_３Ｎ、ＤＭＡＰ；ｂ）ＮａＨＣＯ_３、エタノール、還流；ｃ）ＮａＳＨ、ＤＭＦ
２’－Ｃ－メチル－２－チオウリジンヌクレオシド類似体は、親ヌクレオシド（１当量）を、不活性雰囲気下、ピリジン：ＤＣＭ（１：１）に溶解した塩化トシル（１．２当量）で処理することにより作製することができる。次いで、得られた５’－トシルヌクレオシド類似体を還流エタノール中重炭酸ナトリウム（５当量）で処理して、２－エトキシヌクレオシドを得ることができる。最後に、所望の２－チオヌクレオシド類似体は、２－エトキシ中間体をＤＭＦなどの極性溶媒中の水硫化ナトリウム（１０当量）で処理することにより得ることができる。

Reagents and conditions: a) tosyl chloride, Et ₃ N, DMAP; b) NaHCO ₃ , ethanol, reflux; c) NaSH, DMF
The 2'-C-methyl-2-thiouridine nucleoside analogs can be made by treating the parent nucleoside (1 equivalent) with tosyl chloride (1.2 equivalents) dissolved in pyridine:DCM (1:1) under an inert atmosphere. The resulting 5'-tosyl nucleoside analog can then be treated with sodium bicarbonate (5 equivalents) in refluxing ethanol to give the 2-ethoxy nucleoside. Finally, the desired 2-thionucleoside analogs can be obtained by treating the 2-ethoxy intermediate with sodium hydrosulfide (10 equivalents) in a polar solvent such as DMF.

[Example 86]
Alternative synthetic route for the synthesis of 2'-C-methyl-2-thiouridine nucleoside analogues

試薬および条件：ａ）ＳｎＣｌ_４、ＤＣＥ、室温；ｂ）ＮＨ_３／ＭｅＯＨ

Reagents and conditions: a) _SnCl4 , DCE, room temperature; b) _NH3 /MeOH

[Example 87]

Persilylated 2-thiouracil was prepared in a round bottom flask under nitrogen with 2-thiouracil (1.99 g, 15.5 mmol), chlorotrimethylsilane (1.55 mL, 12.21 mmol) and bis(trimethylsilyl)amine (46.5 mL, 222 mmol). The mixture was refluxed overnight (16 h) with stirring until all solids had dissolved and a blue-green solution was formed. The mixture was cooled to room temperature and volatiles were removed by rotary evaporation followed by high vacuum to give persilylated 2-thiouracil as a pale blue liquid. This compound was used immediately in the next step.

Freshly prepared persilylated 2-thiouracil 240 (4.22 g, 15.50 mmol) was dissolved in 1,2-dichloroethane (50 mL) with stirring at room temperature under nitrogen. A solution of 241 (4.50 g, 7.75 mmol) in 1,2-dichloroethane (50 mL) was added all at once to the stirred mixture.

To this mixture, _SnCl4 (1.36 mL, 3.03 g, 11.63 mmol) was added dropwise via syringe, and the mixture was stirred at room temperature for 6 h until all starting material was consumed. The mixture was cooled to 0° C., and saturated aqueous _NaHCO3 (125 mL) was added. The mixture was warmed to room temperature and stirred for 30 min. The mixture was extracted with EtOAc (2×200 mL), and the combined organic layers were washed with brine (1×100 mL), dried over _Na2SO4 , filtered, and concentrated by rotary evaporation to give 5.5 g of crude product. The crude material was dissolved in _{dichloromethane} , immobilized on Celite, and subjected to flash chromatography on Combiflash (120 g column, gradient 5 to 50% EtOAc in hexanes) to give 242 (2.41 g, 53%) as a clear sticky solid with a purity of about 90%. This material was used directly in the next step without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 9.37 (br s, 1H), 8.10-8.05 (m, 4H), 7.82 (d, J=7.7 Hz, 2H), 7.70 (d, J=8.3 Hz, 1H), 7.66-7.45 (m, 6H), 7.42 (t, J=7.8 Hz, 2H), 7.27-7.21 (m, 2H), 5.88 (d, J=8.2, 1H), 5.62 (d, J=5.5 Hz, 1H), 4.91-4.83 (m, 2H), 4.77 (dd, J=11.8 Hz, 4.7 Hz, 1H), 1.77 (s 3H).

[Example 88]

A round bottom flask was charged with 242 (2.41 g, 4.11 mmol) under nitrogen and cooled to 0° C. To this flask was added a 7.0 N solution of ammonia in methanol (58.7 mL, 411 mmol) and the mixture was gently stirred and allowed to warm to room temperature overnight. After stirring at room temperature for 24 h, the volatiles were removed by rotary evaporation to give 2.5 g of crude material. The crude material was dissolved in MeOH, immobilized on Celite, and subjected to flash chromatography on Combiflash (80 g column, gradient 0 to 10% EtOH in EtOAc) to give 243 (0.873 g, 41% yield for two steps from scaffold) as an off-white solid. ^1H NMR (400MHz, MeOH- _d4 ) δ ppm 8.27 (d, J = 8.2 Hz, 1H); 6.95 (s, 1H), 5.95 (d, 1H, J = 8.1 Hz), 3.98 (dd, J = 12.5 Hz, 2.1 Hz, 1H), 3.93 (dt, J = 9.3 Hz, 2.1 Hz, 1H), 3.84 (d, J = 9.4 Hz, 1H), 3.78 (dd, J = 12.5 Hz, 2.3 Hz), 1.24 (s, 3H).

[Example 89]
General Procedure for the Preparation of 5'-Phosphoramidate Prodrugs Synthesis of Chlorophosphoramidates:

Thionyl chloride (80 g, 49.2 mL, 673 mmol) was added dropwise over 30 min to a suspension of L-alanine (50 g, 561 mmol) in isopropanol (500 mL). The mixture was heated at gentle reflux for 5 h and then concentrated by rotary evaporation (bath set at 60° C.). The resulting thick gum solidified upon trituration with ether (150 mL). The white powder was triturated with a second portion of ether (150 mL), collected by filtration under a stream of argon, and then dried under high vacuum for 18 h to give (S)-isopropyl 2-aminopropanoate hydrochloride (88 g, 94%).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (s, 3H), 5.10-4.80 (m, 1H), 3.95 (q, J = 7.2 Hz, 1H), 1.38 (d, J = 7.2 Hz, 3H), 1.22 (d, J = 4.6 Hz, 3H), 1.20 (d, J = 4.6 Hz, 3H).

[Example 90]

A solution of phenyl dichlorophosphate (30.9 g, 146 mmol) in dichloromethane (450 mL) was cooled to 0° C. and then treated with (S)-isopropyl 2-aminopropanoate hydrochloride (24.5 g, 146 mmol). The mixture was further cooled to −78° C. and then treated dropwise over 30 minutes with triethylamine (29.6 g, 40.8 mL, 293 mmol). The mixture was continued to stir at −78° C. for an additional 2 hours and then allowed to warm slowly to room temperature. After 18 hours, the mixture was concentrated to dryness and the resulting gum was dissolved in anhydrous ether (150 mL). The slurry was filtered under a stream of argon and the collected solid was washed with small amounts of anhydrous ether (3×30 mL). The combined filtrates were concentrated to dryness by rotary evaporation to give a 1:1 diastereomeric mixture of phosphochloridates (41.5 g, 93%) as a pale yellow oil.
^1H NMR (300 MHz, chloroform-d) δ 7.43-7.14 (m, 5H), 5.06 (m, 1H), 4.55 (dd, J=14.9, 7.0 Hz, 1H), 4.21-4.01 (m, 1H), 1.48 (d, J=7.0 Hz, 2H), 1.27 (d, J=6.2 Hz, 3H), 1.26 (d, J=5.8 Hz, 3H).
^31P NMR (121MHz, chloroform-d) δ 8.18 and 7.87.

[Example 91]
Synthesis of 2-chloro-4-nitrophenyl phosphoramidate:

A solution of phenyl dichlorophosphate (60 g, 42.5 mL, 284 mmol) in dichloromethane (300 mL) was cooled to 0° C. and then treated with (S)-isopropyl 2-aminopropanoate hydrochloride (47.7 g, 284 mmol). The mixture was further cooled to −78° C. and treated dropwise over 1 h with a solution of triethylamine (57.6 g, 79 mL, 569 mmol) in methylene chloride (300 mL). The reaction mixture was warmed to 0° C. for 30 min and then treated with a preformed mixture of 2-chloro-4-nitrophenol (46.9 g, 270 mmol) and triethylamine (28.8 g, 39.6 mL, 284 mmol) in dichloromethane (120 mL) over 20 min. After 2 h at 0° C., the mixture was filtered through a fritted funnel and the collected filtrate was concentrated to dryness. The crude gum was dissolved in MTBE (500 mL) and washed with 0.2 M _K2CO3 (2 x 100 mL) followed by 10% brine (3 x 75 mL). The organic phase was dried over sodium sulfate, filtered and rotary evaporated _to dryness to give the diastereomeric mixture (100 g, 93%) as a pale yellow oil.
^1H NMR (400MHz, chloroform-d) δ 8.33 (dd, J = 2.7, 1.1Hz, 1H, diastereomer 1), 8.31 (dd, J = 2.7, 1.1Hz, 1H, diastereomer 2), 8.12 (dd, J = 9.1, 2.7Hz, 1H), 7.72 (dt, J = 9.1, 1.1Hz, 1H), 7.40-7.31 (m, 2H), 7.28-7.19 (m, 6H). H), 5.01 (pd, J = 6.3, 5.2 Hz, 1H), 4.22-4.08 (m, 1H), 3.96 (td, J = 10.7, 9.1, 3.6 Hz, 1H), 1.43 (dd, J = 7.0, 0.6 Hz, 3H), 1.40 (dd, J = 7.2, 0.6 Hz, 3H, diastereomer 2), 1.25-1.20 (m, 9H).

[Example 92]
Separation of Compound 253 diastereomers:

The diastereomeric mixture 253 (28 g, 63.2 mmol) was dissolved in 2:3 ethyl acetate:hexane (100 mL) and cooled to −20° C. After 16 h, the resulting white solid was collected by filtration and dried under high vacuum to give a 16:1 S _p :R _p -diastereomeric mixture (5.5 g, 19.6%). The mother liquor was concentrated and the resulting residue was dissolved in 2:3 ethyl acetate:hexane (50 mL). After 16 h at −10° C., the resulting white solid was collected and dried under high vacuum to give a 1:6 S _p :R _p -diastereomeric mixture (4 g, 14%). The 16:1 S _p :R _p -diastereomeric mixture (5.5 g, 12.4 mmol) was suspended in hot hexane (50 mL) and slowly treated with ethyl acetate (approximately 10 mL) until complete dissolution. After cooling to 0° C., the resulting white solid was collected by filtration, washed with hexanes, and dried under high vacuum to give the S _p -diastereomer of 254 (4.2 g, 76%) as a single isomer.
^1H NMR ( _Sp -diastereomer, 400MHz, chloroform-d) δ 8.33 (dd, J=2.7, 1.1 Hz, 1H), 8.12 (dd, J=9.1, 2.7 Hz, 1H), 7.71 (dd, J=9.1, 1.2 Hz, 1H), 7.41-7.30 (m, 2H), 7.29-7.11 (m, 3H), 5.00 (m, 1H), 4.25-4.07 (m, 1H), 3.97 (dd, J=12.7, 9.4 Hz, 1H), 1.43 (d, J=7.0 Hz, 3H), 1.23 (d, J=2.2 Hz, 3H), 1.21 (d, J=2.2 Hz, 3H).

A 1:6 mixture of S _p :R _p -diastereomers (4 g, 12.4 mmol) was suspended in hot hexane (50 mL) and slowly treated with ethyl acetate (ca. 5 mL) until complete dissolution. After cooling to 0° C., the resulting white solid was collected by filtration, washed with hexane, and dried under high vacuum to give the R _p -diastereomer of 255 (3.2 g, 80%) as a single isomer. The absolute stereochemistry was confirmed by X-ray analysis.
^1H NMR ( _Rp -diastereomer, 400MHz, chloroform-d) δ 8.31 (dd, J = 2.7, 1.1 Hz, 1H), 8.11 (dd, J = 9.1, 2.7 Hz, 1H), 7.72 (dd, J = 9.1, 1.2 Hz, 1H), 7.42-7.30 (m, 2H), 7.31-7.14 (m, 3H), 5.01 (p, J = 6.3 Hz, 1H), 4.15 (tq, J = 9.0, 7.0 Hz, 1H), 4.08-3.94 (m, 1H), 1.40 (d, J = 7.0 Hz, 3H), 1.24 (d, J = 3.5 Hz, 3H), 1.22 (d, J = 3.5 Hz, 3H).

[Example 93]
General Procedure for Phosphoramidate Prodrug Formation:
The desired nucleoside (1 eq.) to be converted to a 5'-phosphoramidate prodrug was dried overnight at 50°C in a vacuum oven. The dried nucleoside was placed in a dry flask under an inert atmosphere and suspended in either dry THF or dry DCM to a 0.05M solution. The flask was then cooled to 0°C and the chlorophosphoramidate reagent (5 eq.) was added to the suspended nucleoside. 1-Methylimidazole (8 eq.) was then added dropwise to the reaction mixture. The reaction was stirred at room temperature for 12-72 hours. After the reaction was complete as judged by TLC, the reaction mixture was diluted with ethyl acetate. The diluted reaction mixture was then washed with saturated aqueous ammonium chloride. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were then washed with brine, dried over _MgSO4 , filtered and concentrated. The concentrated crude product was then purified on silica eluting with a gradient from DCM to 5% MeOH in DCM.

[Example 94]
5'-Phosphoramidate prodrugs synthesized using a general procedure:

[Example 95]
Procedure for the synthesis of 2'-C-methyl-2-thiouridine-5'-phosphoramidate:

The desired nucleoside (1 equiv.) to be converted to the 5'-phosphoramidate prodrug was dried overnight in a vacuum oven at 50°C. To a stirred solution of 1-((2R,3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (100 mg, 0.365 mmol) in THF (4 ml) at 0°C under nitrogen was added (2S)-isopropyl 2-((chloro(phenoxy)phosphoryl)amino)propanoate (334 mg, 1.094 mmol) in THF (2.000 ml) dropwise via syringe. The stirred mixture was treated with 1-methyl-1H-imidazole (0.145 ml, 1.823 mmol) dropwise via syringe over 5 min. The mixture was allowed to warm slowly to room temperature and stirred overnight. After stirring for 20 hours, the mixture was concentrated by rotary evaporation and dissolved in 2 mL of EtOH. A quick column on the Isco (12 g column, 0-3% EtOH in EtOAc) removed most of the baseline impurities to give 220 mg of compound. A second column on the Isco (12 g column, 0-3% EtOH in EtOAc) removed less polar impurities, but more polar impurities were streaked with product. A total of 170 mg was recovered. A third column on the Isco (12 g column, 0-10% MeOH in DCM) gave good separation to produce the desired product (93 mg, 0.171 mmol, 46.9% yield).

[Example 96]
Synthesis of the (S,Sp)-diastereomer of compound 275:

To a dry 50 ml flask was added 1-((2R,3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.5 g, 1.823 mmol) and THF (20 ml) and the suspension was cooled in an ice bath under nitrogen. tert-Butyl magnesium chloride (2.260 ml, 2.260 mmol) was added via syringe to form a clear solution. The mixture was stirred at ambient temperature for 30 minutes and cooled back to 0°C. A solution of compound 254 in THF (20 ml) was added via syringe over 10 minutes at 0°C. The resulting yellowish solution was stirred overnight at room temperature.

The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with 5% K2CO3 solution, water and brine, dried and concentrated under reduced pressure to give the crude product. TLC 5% MeOH/DCM: SM Rf=0.25 and product Rf=0.5. The product was purified on ₂₀ g SiO2 and eluted with 500 ml 3% MeOH in DCM. The desired fractions were combined and concentrated to give the product as a single TLC spot. A small portion was dissolved in toluene and allowed to crystallize as a plate by standing at room temperature for several weeks.
¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.76 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.9 Hz, 2H), 7.34-7.13 (m, 3H), 6.98 (s, 1H), 5.87 (d, J = 8.1 Hz, 1H), 5.06-4.89 (m, 1H), 4.53 (ddd, J = 11.8, 5.8, 2.0 Hz, 1H), 4.39 (ddd, J = 11.9, 5.8, 3.3 Hz, 1H), 4.11 (dp, J = 7.9, 2.2 Hz, 1H), 3.92 (dq, J = 9.9, 7.0 Hz, 1H), 3.78 (d, J = 9.4 Hz, 1H), 1.36 (dd, J = 7.2, 1.0 Hz, 3H), 1.24 (s, 3H), 1.23 (d, J = 1.5 Hz, 3H), 1.21 (d, J = 1.5 Hz, 3H).
MS _{calculated for C22H31N3O9PS} [M+H ⁺ ]: _544.1 , found: 544.1.

[Example 97]
Synthesis of the (S,Rp)-diastereomer of compound 275:

To a dry 50 ml flask was added 1-((2R,3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.5 g, 1.823 mmol) and THF (20 ml) and the suspension was cooled in an ice bath under nitrogen. tert-Butyl magnesium chloride (2.260 ml, 2.260 mmol) was added via syringe to form a clear solution. The mixture was stirred at ambient temperature for 30 minutes and cooled back to 0°C. A solution of compound 255 in THF (20 ml) was added via syringe over 10 minutes at 0°C. The resulting yellowish solution was stirred overnight at room temperature.

The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with 5% K2CO3 solution, water and brine, dried and concentrated under reduced pressure to give the crude product. TLC 5% MeOH/DCM: SM Rf=0.25 and product Rf=0.5. The product was purified on ₂₀ g SiO2 and eluted with 500 ml 3% MeOH in DCM. The desired fractions were combined and concentrated to give the product as a single TLC spot.
¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.78 (d, J = 8.1 Hz, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.31-7.14 (m, 3H), 6.98 (s, 1H), 5.91 (d, J = 8.1 Hz, 1H), 4.99 (mz, 1H), 4.60 (ddd, J = 11.9, 4.8, 2.1 Hz, 1H), 4.43 (ddd, J = 11.8, 5.3, 2.6 Hz, 1H), 4.18-3.98 (m, 1H), 3.90 (dq, J = 9.3, 7.2 Hz, 1H), 3.78 (d, J = 9.4 Hz, 1H), 1.32 (dd, J = 7.1, 1.3 Hz, 3H), 1.23 (m, 8H).
MS _{calculated for C22H31N3O9PS} [M+H ⁺ ]: _544.1 , found: 544.1.

[Example 98]
General procedure for the preparation of the 5'-triphosphate:
The nucleoside analog was dried under high vacuum at 50° C. for 18 hours and then dissolved in anhydrous trimethyl phosphate (0.3 M). After addition of proton-sponge® (1.5 molar equivalents), the mixture was cooled to 0° C. and treated dropwise with phosphoryl chloride (1.3 molar equivalents) via microsyringe over 15 minutes. The mixture was allowed to stir at 0° C. for 4-6 hours while being monitored by tlc (7:2:1 isopropanol:conc. NH ₄ OH:water). Once the conversion to the monophosphate was greater than 85%, the reaction mixture was treated with a mixture of bis(tri-n-butylammonium pyrophosphate) (3 molar equivalents) and tributylamine (6 molar equivalents) in anhydrous DMF (1 mL). After monitoring by tlc (11:7:2 NH ₄ OH:isopropanol:water) for 20 min at 0° C., the mixture was treated with 20 mL of a 100 mM solution of triethylammonium bicarbonate (TEAB), stirred at room temperature for 1 h, and then extracted with ether (3×15 mL). The aqueous phase was then purified by anion exchange chromatography on DEAE Sephadex® A-25 resin (11×200 mm) using a buffer gradient of 50 mM (400 mL) to 600 mM (400 mL) TEAB. 10 mL fractions were analyzed by tlc (11:7:2 NH ₄ OH:isopropanol:water). Fractions containing the triphosphate (eluted with 500 mM TEAB) were combined and concentrated by rotary evaporation (bath <25° C.). The resulting solid was reconstituted in DI water (10 mL) and concentrated by lyophilization.

[Example 99]

The triphosphate was prepared according to the general procedure.
Physical data: ¹ H NMR (400 Hz, D ₂ O): δ 1.226 (s, 3H), 1.280 (t, 36H, J=7.2 Hz), 3.202 (q, 24H, J=7.2 Hz), 4.143 (m, 2H), 4.363 (dq, 2H, J ₁ =12.8 Hz, J ₂ =1.2 Hz), 6.006 (s, 1H), 6.666 (d, 1H, J=7.6 Hz), 7.889 (d, 1H, J=7.2 Hz); MS (negative ion): m/z 512.9 (M-H).

[Example 100]

The triphosphate was prepared according to the general procedure.
Physical data: ^1H NMR (400Hz, _D2O ): δ 1.402 (d, 3H, J=23.2Hz), 1.262 (t, 36H, J=7.2Hz), 3.186 (q, 24H, J=7.2Hz), 4.314 (m, 4H), 6.212 (d, 1H, J=18.8Hz), 6.650 (d, 1H, J=7.6Hz), 7.770 (d, 1H, J=7.6Hz); MS (negative ion): m/z 514.9 (M-H).

[Example 101]

Following the general procedure for making triphosphates, ((2R,3S,4R,5R)-3-hydroxy-4-methyl-5-(2-oxo-4-thioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (4 mg, 3.5%) was obtained as a yellow solid as the tetratriethylammonium salt.
^1H NMR (400MHz, _D2O ) δ 7.84 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.29 (d, J = 7.6 Hz, 1H), 4.33 (bs, 2H), 4.13 (t, J = 8.8, 1H), 4.00 (d, J = 7.2 Hz, 1H), 3.21 (q, J = 6.8 Hz, 24H), 2.72-2.64 (m, 1H), 1.27 (t, J = 7.2 Hz, 36H).

[Example 102]

Following the general procedure for making triphosphates, ((2R,3S,4R,5R)-3-hydroxy-4-methyl-5-(4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (69 mg, 44%) was obtained as a white solid as the triple triethylamine salt.
^1H NMR (400MHz, _D2O ) δ 8.07 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.24 (d, J = 7.2 Hz, 1H), 4.35 (bs, 2H), 4.20 (t, J = 8.4 Hz, 1H), 4.03-4.01 (m, 1H), 3.21 (q, J = 7.6 Hz, 18H), 2.80-2.73 (m, 1H), 1.28 (t, J = 7.6 Hz, 27H), 1.00 (d, J = 7.2 Hz, 3H).
³¹ P NMR (121 MHz, D ₂ O) δ-6.03 (d, J=21.1 Hz, γP), -10.52 (d, J=20.2 Hz, αP), -21.76 (t, J=20.7 Hz, βP).
HRMS calculated _{for C10H16N2O13P3S [ M} -H ⁺ _] : _496.9664 , found 496.9586.

[Example 103]
Methods for the synthesis of 2'-C-methyl-2-thiouridine-5'-triphosphate

After drying under high vacuum at 50° C. for 18 hours, 2′-C-methyl-2-thiouridine (29 mg, 0.106 mmol) was dissolved in anhydrous trimethyl phosphate (0.4 mL) and treated with proton-sponge® (34 mg, 0.159 mmol). The mixture was cooled to 0° C. and treated dropwise over 5 minutes via microsyringe with phosphoryl chloride (13 μL, 0.137 mmol, 1.3 equiv). After 2 hours at 0° C., tlc (7:2:1 isopropanol:conc. NH ₄ OH:water) showed mostly starting material, indicating that the parent nucleoside was slow to react under standard conditions. The mixture was then treated incrementally (10 μL/hour) with additional phosphoryl chloride (40 μL, 0.137 mmol, 4 equiv) and after 5 hours tlc showed complete conversion to the monophosphoryl dichloridate intermediate. Still at 0° C., the reaction mixture was treated dropwise with a solution containing bis(tri-n-butylammonium pyrophosphate) (145 mg, 0.264 mmol) and tributylamine (153 μL, 0.634 mmol) in anhydrous DMF (1 mL). After 20 min at 0° C., the mixture was quenched with 20 mL of a 100 mM solution of triethylammonium bicarbonate (TEAB), stirred for 1 h while warming to room temperature, and then extracted with ether (3×15 mL). The aqueous phase was purified by anion exchange chromatography on DEAE Sephadex® A-25 resin (11×200 mm) using a buffer gradient of 50 mM (400 mL) to 600 mM (400 mL) TEAB. An 8 mL fraction was first analyzed by tlc (11:7:2 NH ₄ OH:isopropanol:water), then the fraction containing the triphosphate was further analyzed by phosphorus NMR to ensure that the product was free of inorganic phosphate (the product mixture contained a high concentration of inorganic phosphate because an excess of phosphoryl chloride was required to initiate phosphorylation of this unreactive nucleoside analogue). Fractions containing the pure triphosphate (eluted with 500 mM TEAB) were combined and concentrated by rotary evaporation (bath <25° C.). The resulting solid was reconstituted in DI water (10 mL) and concentrated by lyophilization to give 2'-C-methyl-2'-thiouridine-5'-triphosphate (25 mg, 33%) as the bis(triethylammonium salt.
^1H NMR (400MHz, deuterium oxide) δ 8.01 (d, J=7.9 Hz, 1H), 7.08 (s, 2H), 6.20 (d, J=7.9 Hz, 2H), 4.36 (m, 2H), 4.14 (m, 2H), 3.19 (q, J=7.3 Hz, 12H), 1.27 (t, J=7.3 Hz, 20H).
^31P NMR (162MHz, deuterium oxide) δ-8.81 (d, J=20.6Hz), -13.70 (d, J=19.9Hz), -24.82 (t, J=20.6Hz).
_{HRMS C10H17N2O14P3S} [M _- H ⁺ _] ; calculated: _512.95287 , found: 512.95406.

[Example 104]
Synthesis of nucleotide alaninyl phosphates

試薬および条件：ａ）Ｅｔ_３Ｎ、Ｈ_２Ｏ、３７℃

Reagents and conditions: a) _Et3N , _H2O , 37°C

[Example 105]

The parent nucleotide, 5'-phosphoramidate (0.1 mmol), was suspended in triethylamine (5 mL) and distilled water (5 mL) in a round-bottom flask at room temperature. The reaction mixture was stirred at 37°C for 24 hours, then the solvent was removed under reduced pressure. The crude residue was purified on silica eluting with 2-propanol, water, ammonia (8:1:1). Fractions containing the desired product were pooled and concentrated under reduced pressure to remove most of the volatiles. The remaining aqueous solution was transferred to a vial and then frozen in a dry ice/acetone bath. The material was then lyophilized to give the desired product as a white solid.

[Example 106]
Synthesis of (R)-2,2,2-trifluoro-N-(1-hydroxyoctadecan-2-yl)acetamide

Phytosphingosine (15.75 mmol) was dissolved in EtOH (0.5 M) and ethyl trifluoroacetate (15.75 mmol) was added dropwise. Then NEt ₃ (24.41 mmol) was added and the reaction mixture was stirred overnight. The solvent was removed in vacuum and the residue was dissolved in EtOAc and brine, washed, dried and concentrated. The crude material was a white powder and was good enough to be used in the next step without further purification.
Characterization was in accordance with the literature: Synthesis, 2011, 867.

[Example 107]

The primary alcohol (15.75 _mmol ), DMAP (1.575 mmol) and NEt (39.4 mmol) were dissolved in a mixture of _CH2Cl2 and _DMF (0.18 M) and cooled to 0° C. TBDPSCl (19.69 mmol) was added dropwise, then the solution was allowed to warm to room temperature and stirred overnight.

NH ₄ Cl solution was added to quench. The reaction mixture was extracted with EtOAc and the combined organic layers were washed with water (×2) to remove DMF. It was then dried and concentrated. The column was run with 10-20% EtOAc/Hex to purify the mixture.
Characterization was in accordance with the literature: Synthesis, 2011, 867.

[Example 108]

The diol (12.58 mmol), triphenylphosphine (50.3 mmol) and imidazole (50.03 mmol) were dissolved in toluene and reheated to reflux. Iodine (37.7 mmol) was then added slowly and the reaction mixture was kept stirring at reflux. After 3 hours, it was cooled to room temperature and 1 equivalent of iodine (12.58 mmol) was added followed by 8 equivalents of 1.5 M NaOH (100.64 mmol). The reaction mixture was stirred until all solids were dissolved. The aqueous layer was removed in a separatory funnel and the organic layer was washed with Na ₂ S ₂ O ₃ solution, then NaHCO ₃ solution, then brine. It was dried and concentrated. The mixture was purified by running a column with 0-20% EtOAc/Hex to give a mixture of cis and trans, which was carried on to the next step.
δ ^1H NMR (400MHz, chloroform-d) δ 7.64 (ddt, J=7.8, 3.8, 1.7Hz, 4H), 7.51-7.35 (m, 6H), 6.68 (dd, J=16.0, 8.2Hz, 1H), 5.6-5.40 (m, 2H), 4.57-4.46 (m, 1H), 3.84-3.62 (m, 2H), 2.04 (q, J=7.0Hz, 1H), 1.28-1.21 (m, 24H), 1.15-0.98 (m, 9H), 0.90 (t, J=6.8Hz, 3H).
HRMS: 617.38759.

[Example 109]

The alkene (2.91 mmol) was dissolved in MeOH (0.1 M) and Pd(OH) ₂ /C (0.146 mmol) was added. A Parr hydrogenation apparatus was used at 40 psi. The palladium catalyst was carefully filtered off through Celite and rinsed with EtOAc. The crude material was used in the next step in quantitative yield.

[Example 110]

The silyl ether was dissolved in THF and cooled to 0° C., then TBAF was added dropwise. After stirring for 1 h, it was warmed to room temperature. After 2 h, NH4Cl solution was added and it was extracted with EtOAc, washed with brine, dried and concentrated. The column was run with 10-50% EtOAc/Hex.
^1H NMR (400MHz, chloroform-d) δ 7.60 (tt, J=7.0, 1.5Hz, 2H), 7.48-7.33 (m, 4H), 3.73-3.61 (m, 1H), 1.24 (d, J=3.5Hz, 18H), 1.05 (s, 6H), 0.86 (t, J=6.8Hz, 3H). HRMS: 381.28546.

[Example 111]
Synthesis of 2-amino-octadecyl-FTC-5'-monophosphate conjugate

Step 1:
The alcohol (0.604 mmol) was dissolved in pyridine (0.1 M) and cooled to 0° C., then CBr ₄ (0.755 mmol) was added, followed by P(OMe) ₃ (0.845 mmol) dropwise over 1 h. Once the addition was complete, the mixture was stirred at 0° C. for 1 h and then warmed to room temperature. Water was added to quench and the solvent was removed in vacuo. The residue was dissolved in EtOAc and washed with 3% HCl (×2), then NaHCO ₃ solution, then brine. A poor emulsion developed, especially after the NaHCO ₃ solution wash. It was then dried and concentrated. The column could have been run as some starting material was present as the reaction was not complete, but the crude material was taken to the next step. Phosphate formation was confirmed by ³¹ P NMR and ¹ H NMR.
^1H NMR (300 MHz, chloroform-d) δ 7.55 (d, J = 8.0 Hz, 1H), 4.10 (dq, J = 7.1, 4.4 Hz, 3H), 3.76 (dd, J = 11.2, 4.7 Hz, 6H), 1.67-1.56 (m, 2H), 1.23-1.18 (m, 28H), 0.91-0.76 (m, 3H).
HRMS: 489.28309.

Step 2:
Dimethyl phosphate (0.291 mmol) was dissolved in dry _CH2Cl2 ( _0.1 M), cooled to 0°C using an ice bath, then treated dropwise with TMSBr (1.454 mmol) via syringe pump over 30 min. The mixture was allowed to warm to room temperature for 1 _h . It was concentrated to dryness after 4 h, then coevaporated with 3 x 50 mL of _CH2Cl2 . The crude residue was cooled in an ice bath and treated with an ice-cold mixture of ca. 1% aqueous _NH4OH /THF. The mixture was stirred at 4°C for 10 min, then concentrated to dryness. The crude material was analyzed by ¹ H NMR and ³¹ P NMR, then triturated with methanol/ACN, then filtered. The collected off-white solid was washed with dry acetonitrile.

FTC (0.155 mmol) and phosphate (0.155 mmol) were dissolved in pyridine (0.05 M) and trisyl chloride was added. This was stirred overnight at 50° C. The solvent was removed in vacuo and the crude material was purified by column with 5%-50% MeOH/NH ₄ OH/CHCl ₃ .
¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.15-8.08 (m, 1H), 6.27-6.19 (m, 1H), 5.37 (t, J = 4.0 Hz, 1H), 4.19-4.10 (m, 1H), 4.07 (td, J = 7.7, 5.5, 3.1 Hz, 1H), 3.96-3.83 (m, 2H), 3.29 (s, 1H), 1.58-1.50 (m, 1H), 1.26-1.18 (m, 28H), 0.92-0.83 (m, 3H).
HRMS: 690.28392.

[Example 112]

The phosphate was dissolved in MeOH (0.05 M) and NH ₄ OH in a pressure tube and stirred overnight at 40° C. The reaction was very sluggish and on more than one occasion was not complete after 24 hours, in which case it was resubmitted for an additional 24 hours.
¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.10 (t, J=6.0 Hz, 1H), 6.24 (q, J=5.4 Hz, 1H), 5.49-5.42 (m, 1H), 5.38 (dt, J=9.2, 4.1 Hz, 1H), 4.26-4.10 (m, 2H), 4.07 (q, J=5.0, 4.6 Hz, 1H), 3.95-3.82 (m, 1H), 3.48 (dt, J = 9.5, 4.6 Hz, 1H), 3.32 (d, J = 3.6 Hz, 2H), 3.17 (ddd, J = 12.3, 7.7, 4.3 Hz, 1H), 1.61 (dt, J = 13.0, 7.2 Hz, 2H), 1.25 (d, J = 9.1 Hz, 28H), 0.87 (t, J = 5.7, 4.8 Hz, 3H).
HRMS: 594.30162.

[Example 113]
Synthesis of 2-amino-octadecyl-tenofovir-5'-monophosphate conjugate

Tenofovir (0.149 mmol) and alcohol (0.149 mmol) were dissolved in pyridine (0.05 M) and trisyl chloride (0.448 mmol) was added. This was stirred overnight at 50° C. The solvent was removed in vacuo and the crude material was purified by column with 5%-50% MeOH/NH ₄ OH/CHCl ₃ .
¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.3 (s, 1H), 8.2 (s, 1H), 4.4-3.2 (m, 8H), 1.6 (m, 2H), 1.4-1.1 (m, 31H), 0.9 (t, 3H). HRMS: 650.35324.

[Example 114]

The phosphate was dissolved in MeOH (0.05 M) and NH ₄ OH in a pressure tube and stirred overnight at 40° C. The reaction was very sluggish and on more than one occasion was not complete after 24 hours, in which case it was resubmitted for an additional 24 hours.
¹ H NMR (300 MHz, methanol-d ₄ ) δ 8.31 (d, J=5.4 Hz, 1H), 8.21 (d, J=5.5 Hz, 1H), 4.5-3.2 (m, 10H), 1.63-1.52 (m, 2H), 1.4-1.0 (m, 31H), 0.87 (t, J=6.3 Hz, 3H).
HRMS: 554.37094.

[Example 115]
Synthesis of 2'-fluoro-2'-methyluridine-5'-HDP-monophosphate conjugates

Compound 314 was prepared according to literature procedures (Bioorganic & Medicinal Chemistry 20 (2012) 3658-3665).

Compound 315:
To a solution of 1H-tetrazole (0.415 g, 5.92 mmol) in 25 ml of ether and 10 ml of acetonitrile was added diisopropylamine (0.93 ml, 0.726 g, 7.03 mmol). The precipitate was filtered off, washed with ether and dried under vacuum to give diisopropylammonium tetrazolide.

Compound 316:
3-(Hexadecyloxy)propan-1-ol (0.301 g, 1.00 mmol) and diisopropylammonium tetrazolide (0.115 g, 0.67 mmol) were coevaporated with DCM-AcCN mixture (10:10) three times. The dried mixture was dissolved in 7 ml of DCM and 3-((bis(diisopropylamino)phosphino)oxy)propanenitrile (0.673 ml, 2.120 mmol) was added. After stirring at room temperature for 1 h, 1 ml of methanol was added and stirred for 15 min. The reaction was then concentrated under vacuum; diluted with 10% TEA solution in EtOAc (100 ml), washed with 10% _NaHCO3 solution (2 x 50 ml) and water (2 x 50 ml); dried over anhydrous _MgSO4 ; filtered off and evaporated. The crude product was purified by column chromatography using hexane:EtOAc:TEA (10:4:0.5).
1H-NMR: 3.89-3.54 (m, 6H); 3.49 (t, 2H, J=6.4Hz); 3.39 (t, 2H, J=6.4Hz); 2.63 (dt, 2H, J=1.6, 6.4Hz); 1.89-1.83 (m, 1H); 1.57-1.51 (m, 1H); 1.24 (s, 24H); 1.19-1.16 (m, 16H); 0.87 (t, 3H, J=6.4Hz).

Compounds 317, 318, 319:
Amidophosphite (compound 3) (0.114 g, 0.228 mmol) and 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (0.065 g, 0.248 mmol) were dried by coevaporation with anhydrous DCM (4×10 ml), dissolved in 4 ml of DCM and a 3% solution of 1H-tetrazole in acetonitrile (0.75 ml, 0.320 mmol) was added. After stirring for 1 hour at room temperature, a 5.5 M solution of tert-butyl peroxide (0.25 ml, 1.359 mmol) was added. After 40 minutes the solvent was evaporated and the reaction mixture was dissolved in toluene and 1 ml of TEA was added. This was stirred for 5 hours. All the solvent was evaporated and coevaporated with toluene (2×2 ml). The crude material was purified by column chromatography starting with CHCl ₃ and slowly increasing in polarity with CHCl ₃ :MeOH:NH ₄ OH (75:25:5) to give compound 319.
1H-NMR: (CDCl3-CD3OD, 3:1) 1.024 (t, 3H, 6.4 Hz); 1.35-1.49 (m, 27H); 1.55 (d, 2H, 6.0 Hz); 1.63-1.70 (m, 2H); 2.011-2.067 (m, 2H); 3.47-3.49 (m, 2H); 3. 54 (q; 2H, J=4.8 Hz); 3.65-3.70 (m, 2H); 4.07-4.20 (m, 3H); 4.23-4.42 (m, 2H); 5.99 (d, 1H, J=8.4 Hz); 6.32 (dd, 1H, J=19.2, 5.2 Hz); 8.125 (t, 1H, J=8.0 Hz).
^31P -NMR: (CDCl3-CD3OD, 3:1) 17.95 ppm.
HRMS: 623.34722.

[Example 116]
Synthesis of 2'-deoxy-2'-beta-methyl-2-thiouridine

The nucleoside (4.15 g, 15.13 mmol) was dried by azeotroping residual water by dissolving in pyridine and removing volatiles by rotary evaporation (3 x 50 mL). The residue was dissolved in pyridine (200 mL) under nitrogen at 0°C with stirring and 1,3-dichloro-1,1,3-3-tetraisopropyldisiloxane (5.81 mL, 18.2 mmol) was added dropwise via syringe over 5 minutes. The mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was then concentrated by rotary evaporation and dissolved in CH ₂ Cl ₂ (500 mL). The solution was washed with saturated aqueous NaHCO ₃ (2 x 500 mL) then dried over Na ₂ SO ₄ , filtered and concentrated by rotary evaporation to give 12 g of crude material. The mixture was dissolved in CH ₂ Cl ₂ and flash chromatography on a CombiFlash (120 g column, gradient 5 to 30% EtOAc in hexanes) afforded 320 (6.55 g, 84%) as a white powdery solid.
^1H NMR (400MHz, _CDCl3 ) δ 9.29 (br s, 1H), 7.81 (d, J = 8.2 Hz, 1H), 6.87 (br s, 1H), 5.97 (d, J = 8.1 Hz, 1H), 4.24 (d, J = 13.6 Hz, 1H), 4.10 (dd, J = 9.1 Hz, 2.6 Hz, 1H), 4.02 (dd, J = 13.6 Hz, 2.8 Hz, 1H), 3.99 (d, J = 9.1 Hz, 1H), 1.33 (s, 3H), 1.14-1.05 (m, 28H).

[Example 117]

To a stirred solution of 320 (6.25 g, 12.09 mmol) and 4-DMAP (2.95 g, 24.19 mmol) in acetonitrile (121 mL) at room temperature under nitrogen, methyl-2-chloro-2-oxoacetate (1.67 mL, 18.14 mmol) was added dropwise via syringe. The mixture was stirred at room temperature for 2 h and then diluted with EtOAc (600 mL). The organic solution was washed successively with saturated aqueous _NaHCO3 , water and brine (1 x 120 mL each), dried over _MgSO4 , filtered and concentrated by rotary evaporation. The resulting crude was dried under high vacuum overnight to give 321 (7.60 g) as a pale yellow solid. The entire crude product mixture was carried onto the next step without further purification.
^1H NMR (400MHz, _CDCl3 ) δ 7.82 (1H, d, J = 8.2 Hz), 7.12 (s, 1H), 5.99 (d, J = 8.2 Hz, 1H), 4.25-4.18 (m, 2H), 4.10 (d, J = 9.3 Hz, 1H), 4.02 (dd, J = 13.7 Hz, 2.8 Hz, 1H), 3.91 (s, 3H), 1.86 (s, 3H), 1.15-0.90 (m, 28H).

[Example 118]

To a stirred solution of crude 321 (7.60 g) and tributyltin hydride (4.89 mL, 18.14 mmol) in toluene (216 mL) refluxed under nitrogen, solid AIBN (0.397 g, 2.42 mmol) was added all at once. The mixture was heated to reflux for 2 h and then cooled to room temperature. Volatiles were removed by rotary evaporation and the crude residue was dissolved in a small amount of PhMe. Flash chromatography on a Combiflash (120 g column, gradient 1 to 30% EtOAc in hexanes) afforded 322 (5.30 g, ∼79% yield) as a white solid of ∼90 purity (the remainder being tributylstannane residues). NMR analysis indicated a 10:1 β:α dr at the _C2 ′ position. This almost pure product was carried on in its entirety to the next step without further purification.
Major isomer ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.37 (br s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 7.5 Hz, 1H), 5.96 (dd, J = 8.0 Hz, 2.1 Hz, 1H), 4.17 (d, J = 13.2 Hz, 1H), 4.03 (dd, J = 13.5 Hz, 2.8 Hz, 1H), 3.98 (t, J = 9.6 Hz, 1H), 3.78 (ddd, J = 8.8 Hz, 2.8 Hz, 1.0 Hz), 2.74 (m, 1H), 1.15-0.95 (m, 31H). Signals of minor isomers were also seen in ¹ H NMR (400 MHz, CDCl ₃ ). δ 8.08 (d, J = 8.2 Hz, 1H), 4.38 (dd, J = 9.1 Hz, 7.5 Hz, 1H), 4.24 (d, J = 12.9 Hz, 1H), 2.53 (m, 1H).

[Example 119]

To a stirred solution of 322 (5.30 g, 10.58 mmol) in THF (106 mL) at 0° C. under nitrogen, a solution of TBAF (1.0 M in THF, 21.17 mL) was added dropwise via syringe. The mixture was brought to room temperature and stirred for 2 h. The volatiles were removed by rotary evaporation to give a crude yellow oil. The material was dissolved in EtOAc and flash chromatography on a Combiflash (330 g column, gradient 0 to 5% MeOH in DCM) gave 2.8 g of mostly purified material as a white solid. This material was dissolved in methanol, immobilized on Celite, then loaded onto the top of a column of 10% w/w KF/silica. Flash chromatography (10% MeOH in EtOAc) gave 323 (1.96 g, 63% yield over three steps) as a white solid. ¹ H NMR analysis showed a 13:1 β:α dr at the C ₂ ' position (integral of the methyl doublet).
Major isomer ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.18 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 5.95 (d, J = 8.2 Hz, 1H), 3.93 (dd, J = 12.2 Hz, 2.1 Hz, 1H), 3.89 (t, J = 8.2 Hz, 1H), 2.64 (m, 1H), 0.99 (d, 7.1 Hz, 3H). ES+APCI (70 eV) m/z: [M+ _HCO2 ] ^-302.9 .

[Example 120]
Synthesis of 2'-deoxy-2'-fluoro-2-thiouridine

2'-Deoxy-2'-fluorouridine (4.92 g, 20.0 mmol) was dissolved in pyridine and dried by azeotroping residual water by removing volatiles by rotary evaporation (3 x 50 mL). The residue was dissolved in pyridine (100 mL) with stirring at 0 °C under nitrogen and 1,3-dichloro-1,1,3-3-tetraisopropyldisiloxane (7.68 mL, 24.0 mmol) was added dropwise via syringe over 5 min. The mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was then concentrated by rotary evaporation and dissolved in CH ₂ Cl ₂ (500 mL). The solution was washed with saturated aqueous NaHCO ₃ (2 x 500 mL) then dried over Na ₂ SO ₄ , filtered, and concentrated by rotary evaporation to give 324 (9.09 g, 93% yield) as a white solid with purity >95% by NMR analysis.
^1H NMR (400MHz, _CDCl3 ) δ 8.07 (br s, 1H), 7.81 (d, J = 8.2 Hz, 1H), 5.90 (d, J = 16.2 Hz, 1H), 5.71 (dd, J = 8.2 Hz, 2.3 Hz, 1H), 4.90 (dd, J = 53.2 Hz, 3.4 Hz, 1H), 4.30 (ddd, J = 28.2 Hz, 9.6 Hz, 3.6 Hz, 1H), 4.29 (d, J = 14.3 Hz, 1H), 4.16 (d, J = 10.6 Hz, 1H), 4.02 (dd, J = 13.6 Hz, 2.5 Hz, 1H), 1.15-1.00 (m, 28H).

[Example 121]

To a vigorously stirred biphasic mixture of 324 (4.89 g, 10.0 mmol) in CH ₂ Cl ₂ (200 mL) and 0.2 M Na ₂ CO ₃ (400 mL) at room temperature was added solid n-Bu ₄ Br (1.29 g, 4.00 mmol) followed by 2,4,6-triisopropylbenzene-1-sulfonyl chloride (3.94 g, 13.0 mmol). The mixture was vigorously stirred at room temperature for 20 h after which the organic layer was removed and the aqueous layer was extracted with CH ₂ Cl ₂ (2×250 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated by rotary evaporation followed by azeotropic removal of water by coevaporation with PhMe (100 mL) to give crude 325 as a yellow oil that also contained residues from excess reagents. The entire crude was carried on to the next step without further purification.
^1H NMR (400MHz, _CDCl3 ) δ 8.28 (d, J = 7.3 Hz, 1H), 7.23 (s, 2H), 6.04 (d, J = 7.4 Hz, 1H), 5.86 (d, J = 15.2 Hz, 1H), 4.92 (dd, J = 52.4 Hz, 2.9 Hz, 1H), 4.30-4.05 (m, 5H), 3.99 (dd, J = 13.7 Hz, 2.3 Hz, 1H), 3.0-2.85 (m, 1H), 1.35-1.25 (m, 18H), 1.15-1.00 (m, 28H).

[Example 122]

To a stirred solution of crude 325 in MeCN (100 mL) at room temperature under nitrogen was added a solution of 2,6-dimethylphenol (1.22 g, 10.0 mmol), triethylamine (4.18 mL, 30.0 mmol) and DABCO (0.112 g, 1.00 mmol) in MeCN dropwise over 30 min. The mixture turned deep red immediately upon the start of the addition and was stirred for an additional 90 min after the addition was complete. The reaction mixture was concentrated by rotary evaporation and the residue was redissolved in CHCl ₃ (300 mL). The solution was washed successively with saturated aqueous NaHCO ₃ (1×300 mL) and brine (2×300 mL), dried over Na ₂ SO ₄ , filtered and concentrated by rotary evaporation to give a crude red oil. Flash chromatography on a Combiflash (330 g column, gradient 5 to 20% EtOAc in hexanes) afforded 326 (5.02 g, 85% yield over two steps) as an off-white solid foam.
^1H NMR (400MHz, _CDCl3 ) δ 8.20 (d, J = 7.4 Hz, 1H), 7.06 (s, 3H), 6.08 (d, J = 7.4 Hz, 1H), 5.94 (d, J = 15.9 Hz, 1H), 5.02 (dd, J = 52.1 Hz, 3.1 Hz, 1H), 4.31 (d, J = 13.8 Hz, 1H), 4.32-4.18 (m, 2H), 4.03 (dd, J = 13.6 Hz, 2.0 Hz, 1H), 2.13 (s, 6H), 1.15-0.97 (m, 28H).

[Example 123]

To a stirring solution of 326 (4.50 g, 7.59 mmol) in PhMe (76 mL) under nitrogen, Lawesson's reagent (4.61 g, 11.39 mmol) was added all at once as a solid. The mixture was refluxed with stirring under nitrogen for 2 h and then cooled to room temperature. The mixture was filtered through Celite and the pad was rinsed with PhMe (2 x 30 mL). The combined filtrates were concentrated by _rotary evaporation and the crude residue was dissolved in _CH2Cl2 and flash chromatography on a CombiFlash (120 g column, gradient 1 to 15% EtOAc in hexanes) afforded 327 (2.80 g, 55% yield) as a fluffy yellow solid in approximately 90% purity as determined by ^1H NMR analysis.
^1H NMR (400MHz, _CDCl3 ) δ 8.46 (d, J = 7.5 Hz, 1H), 7.08 (s, 3H), 6.57 (d, J = 14.6 Hz, 1H), 6.26 (d, J = 7.5 Hz, 1H), 5.23 (dd, J = 51.3 Hz, 3.4 Hz, 1H), 4.35-4.25 (m, 2H), 4.16 (ddd, J = 29.4 Hz, 10.3 Hz, 3.9 Hz, 1H), 4.03 (dd, J = 13.8 Hz, 2.5 Hz, 1H), 2.14 (s, 6H), 1.15-0.95 (m, 28H).

[Example 124]

To a stirred solution of 327 (2.70 g, 4.43 mmol) in MeCN (44 mL) at room temperature under nitrogen was added a solution of 1,1,3,3-tetramethylguanidine (1.67 mL, 13.3 mmol) and (Z)-2-nitrobenzaldehyde oxime (2.21 g, 13.3 mmol) in MeCN (44 mL) dropwise via syringe over 5 min. The mixture was stirred for 20 h and then diluted with CHCl ₃ (450 mL). The solution was washed with saturated aqueous NaHCO ₃ (1×450 mL) and brine (1×450 mL), dried over Na ₂ SO ₄ , filtered, and concentrated by rotary evaporation. Flash chromatography on a CombiFlash (40 g column, gradient 1 to 25% EtOAc in hexanes) afforded an inseparable mixture of 328 and nitrobenzaldehyde oxime (approximately 5:3 molar ratio by NMR) as a yellow oil, which was carried on in its entirety to the next step without further purification.
^1H NMR (400MHz, _CDCl3 ) δ 9.72 (br s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 6.47 (d, J = 14.6 Hz, 1H), 5.98 (d, J = 8.4 Hz, 1H), 5.03 (dd, J = 51.8 Hz, 3.4 Hz, 1H), 4.32 (d, J = 13.7 Hz, 1H), 4.24 (dt, J = 9.8 Hz, 1.8 Hz, 1H), 4.16 (ddd, J = 28.0 Hz, 9.7 Hz, 3.3 Hz, 1H), 4.02 (dd, J = 13.7 Hz, 2.3 Hz, 1H), 1.15-0.95 (m, 28H).

To a stirred solution of 328 in THF (44 mL) at 0° C. under nitrogen, a solution of TBAF (8.86 mL, 1.0 M in THF, 8.86 mmol) was added dropwise via syringe over 5 min. The mixture was warmed to room temperature and stirred for 1 h. The mixture was concentrated by rotary evaporation, the crude residue was dissolved in EtOAc, and bulk impurities were removed by flash chromatography on a Combiflash (80 g column, 10% MeOH in EtOAc) to give 1.8 g of impure product. The mixture was redissolved in MeOH and immobilized on Celite. A second flash chromatography column on a Combiflash (80 g, gradient 1 to 10% MeOH in EtOAc) gave 329 (0.940 g, 81% yield over two steps) as a white solid.
^1H NMR (400MHz, MeOH- _d4 ) δ 8.36 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 15.6 Hz, 1H), 5.94 (d, J = 8.2 Hz, 1H), 5.03 (dd, J = 52.0 Hz, 4.0 Hz, 1H), 4.24 (ddd, J = 24.2 Hz, 9.0 Hz, 4.1 Hz, 1H), 4.08 (d, J = 8.9 Hz, 1H), 4.03 (d, J = 12.7 Hz, 1H), 3.81 (dd, J = 12.6 Hz, 2.2 Hz, 1H).
ES+APCI(70 eV) m/z: [M+H] ⁺ 263.0.

[Example 125]
Synthesis of α-boranotriphosphate analogues

The nucleosides for conversion were dried overnight at 60°C in a vacuum oven. The dried nucleosides were suspended in dry THF in a drying flask under argon atmosphere. The suspension was then treated with 2-chloro-4H-1,2,3-benzodioxaphosphorin-4-one and tributylamine. After consumption of the starting material, 0.5 M tributylammonium pyrophosphate solution in DMF and tributylamine was added. Then, 2.0 M dimethylsulfide borane complex in THF was added. The reaction mixture was quenched with triethylamine/water (3:2) mixture. The desired product was purified on a DEAE column eluting with triethylammonium bicarbonate solution.

[Example 126]
Synthesis of Nucleotide Amino Acid Boranophosphoramidate Analogues.

L-Alanine isopropyl ester hydrochloride (0.5 mmol) was suspended in dry DCM in a dry flask under argon atmosphere and treated with DIPEA (1 mmol). After a clear solution was formed, 2-chloro-1,3,2-oxathiaphospholane 333 (0.55 mmol) was added. After stirring for 30 min at room temperature, borane-dimethylsulfide complex (2.5 mmol) was added. The reaction was stirred for an additional 30 min. Next, nucleoside (0.4 mmol) and DBU (1.5-5 equiv.) in dry acetonitrile were added to the reaction. The reaction was quenched with triethylamine/water (1:1 v/v) for 15 min with stirring. The solvent was then reduced under reduced pressure. The residue was then coevaporated with ethanol (3 x 15 mL). The desired product was purified on silica eluting with methanol (3-15%) in DCM containing 0.5% triethylamine.

[Example 127]
Synthesis of 3'-fluoro-2'-substituted ribonucleoside analogues

[Example 128]

[Example 129]
Synthesis of 3'-substituted ribonucleoside analogues

[Example 130]

[Example 131]

To a solution of 33.4 g of sodium ethoxide in ethanol (21 wt%), diethyl malonate (15 g) was added dropwise followed by 1-bromohexadecane (31.5 g). After refluxing for 8 h, the ethanol was evaporated in vacuum. The remaining suspension was mixed with ice water (200 ml) and extracted with diethyl ether (3 x 200 ml). The combined organic layers were dried over _MgSO4 , filtered and the filtrate was evaporated in vacuum to give a viscous oily residue. This residue was purified by column chromatography (silica: 500 g) using hexane/diethyl ether (12:1) as the mobile phase to give the main compound.

[Example 132]

In a 250 mL round bottom flask was lithium aluminum hydride (2.503 g, 66.0 mmol) in diethyl ether (90 ml) to obtain a suspension. To this suspension was added diethyl 2-hexadecylmalonate (18.12 g, 47.1 mmol) dropwise and the reaction was refluxed for 6 h. The reaction was followed by TLC using PMA and H2SO4 as drying agents. Excess lithium aluminum hydride was destroyed with 200 ml ice water. 150 ml of 10% H2SO4 was added to dissolve the aluminum hydrate. The reaction mixture was extracted with diethyl ether (100 ml x 3). The organic layer containing the undissolved product was filtered. The collected solid was washed with ethyl acetate. The filtrate was dried over _MgSO4 , filtered and concentrated under reduced pressure. The product was purified on a silica (100 g) column eluted with hexane:EtOAc (3:1 to 1:1).

[Example 133]

To a solution of 2-hexadecylpropane-1,3-diol (7.04 g, 23.43 mmol) in 100 ml of DCM was added phosphorus trichloride (3.59 g, 23.43 mmol) dissolved in 20 ml of DCM dropwise, followed by triethylamine (6.53 ml, 46.9 mmol). The reaction was refluxed for 1 hour. TLC analysis showed that the starting material had been consumed and two new spots had formed. The mixture was concentrated to dryness, dissolved in dry diethyl ether, and filtered. The filtrate was concentrated to give the crude product (8.85 g), which was used in the next step without further purification.

[Example 134]
Synthesis of 5'-deuterated nucleoside analogues

The nucleoside was suspended in methylene chloride (40 mL, partially soluble). After stirring at room temperature for 30 minutes, the mixture was treated sequentially with PDC, acetic anhydride, and then tert-butanol. The mixture was continued to stir at room temperature. TLC (5% methanol in DCM) and LCMS showed only a small amount of starting material remaining at the 4 hour mark. The mixture was filtered through a pad of silica gel and the pad was loaded into a 150 mL fritted funnel. The silica was eluted with ethyl acetate. The collected filtrate was concentrated under reduced pressure. The crude dark oil was purified by chromatography on silica gel (25 mm x 175 mm) using a gradient of 2:1 hexane:ethyl acetate to ethyl acetate. Pure fractions were collected and concentrated to give a white gum. The material was placed under high vacuum for 2 days and used in the next step without further purification.

The 5'-protected nucleoside was dissolved in 200 proof ethanol and then treated with solid sodium borodeuteride. The mixture became homogeneous and was then heated to 80°C. After 12 hours, a white/light yellow precipitate formed. The mixture was cooled to room temperature. TLC (5% methanol in methylene chloride) showed complete conversion of the starting material. The mixture was cooled to 0°C using an ice bath and then slowly quenched with acetic acid (~1 mL). The clear solution was allowed to warm to room temperature and then partitioned between ethyl acetate (30 mL) and brine (3 mL). The organic phase was concentrated and then purified by chromatography on silica gel (19 mm x 180 mm) using a mobile phase of 5% methanol in methylene chloride.

[Example 135]
Synthesis of 1'-deuterated nucleoside analogues

The lactone (0.0325 mol) was added to a dry flask under an argon atmosphere and then dissolved in dry THF (250 mL). The solution was then cooled to -78°C and a solution of DIBAL-D (0.065 mol) in toluene was added dropwise. The reaction was stirred at -78°C for 3-4 hours. The reaction was then quenched by slow addition of water (3 mL). The reaction was then stirred while warming to room temperature. The mixture was then diluted with 2 volumes of diethyl ether and then poured into an equal volume of saturated sodium potassium tartrate solution. The organic layer was separated, dried over _MgSO4 , filtered and concentrated under reduced pressure. The residue was purified on silica eluting with hexanes/ethyl acetate.

[Example 136]
Synthesis of 4'-Substituted Nucleoside Analogues

[Example 137]

1-(4'-azido-5'-O-(3-chloro)benzoyl-2',3'-O-dibenzoyl-β-D-ribofuranosyl)4-thiouracil (396):
A pear-shaped flask was charged with 1-(4'-azido-5'-O-(3-chloro)benzoyl-2',3'-O-dibenzoyl-β-D-ribofuranosyl)uracil (1.08 g, 1.709 mmol), Lawesson's reagent (0.76 g, 1.88 mmol), and THF (40 mL) under a nitrogen atmosphere, and the flask was placed in a 55°C oil bath. The reaction was monitored by TLC and was complete after approximately 4 hours. The mixture was then concentrated by rotary evaporation to give an oil, which was purified by silica gel chromatography (20-25% EtOAc in hexanes) to give 1-(4'-azido-5'-O-(3-chloro)benzoyl-2',3'-O-dibenzoyl-β-D-ribofuranosyl)4-thiouracil (1.04 g, 94%) as a yellow solid. ^1H NMR (400MHz, _CDCl3 ); δ 9.51 (br s, 1H), 8.04-7.91 (m, 5H), 7.59-7.51 (m, 3H), 7.41-7.30 (m, 6H), 7.06 (d, J = 7.6 Hz, 1H), 6.40 (d, J = 7.6 Hz, 1H), 6.25 (d, J = 7.6 Hz, 1H), 5.97 (dd, J = 2.4, 7.6 Hz, 1H), 5.86 (d, J = 2.4 Hz, 1H), 4.82 (d, J = 12.0 Hz, 1H), 4.77 (d, J = 12.0 Hz, 1H).

1-(4'-azido-β-D-ribofuranosyl)4-thiouracil (397):
To a stirred solution of 1-(4'-azido-5'-O-(3-chloro)benzoyl-2',3'-O-dibenzoyl-β-D-ribofuranosyl)4-thiouracil (1.04 g, 1.605 mmol) in methanol (32 ml) at 0° C. was added methanolic ammonia (7 mL, 7 M in MeOH). The mixture was allowed to warm to room temperature and stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (5-8%) in methylene chloride] to give pure 1-(4'-azido-β-D-ribofuranosyl)4-thiouracil (410 mg, 85%) as a yellow solid. ^1H NMR (400MHz, _CD3OD ); δ 7.71 (d, J = 8.0Hz, 1H), 6.37 (d, J = 8.0Hz, 1H), 6.13 (d, J = 5.2Hz, 1H), 4.38 (t, J = 5.2Hz, 1H), 4.30 (d, J = 5.2Hz, 1H), 3.67 (d, J = 12.0Hz, 1H), 3.58 (d, J = 12.0Hz, 1H) ^.13C NMR (100MHz _, CD3OD); δ 192.4, 149.8, 136.6, 114.7, 100.8, 92.1, 74.6, 73.3, 64.9. HRMS (ESI ₎ calculated for _{C9H11O5N5NaS [} M ₊ Na] ⁺ : 324.0373. Found: 324.0372.

[Example 138]

A round bottom flask was charged with 2-thiouracil (1.28 g, 10.0 mmol), (NH ₄ ) ₂ SO ₄ (66 mg, 0.50 mmol) and bis(trimethylsilyl)amine (21 mL, 100 mmol) under nitrogen. The mixture was refluxed with stirring overnight (16 h) until a blue-green solution formed. The mixture was cooled to room temperature and the volatiles were removed by rotary evaporation followed by high vacuum to give the persilylated 2-thiouracil as a pale blue liquid. The yield was assumed to be quantitative and this compound was used immediately in the next step.

A solution of 398 (2.19 g, 5.00 mmol) in 1,2-dichloroethane (50 mL) was added to the freshly prepared 240 under nitrogen and the resulting cloudy mixture was cooled to 0 °C with stirring. Tin(IV) chloride (1.17 mL, 10.0 mmol) was added to the stirred mixture via syringe over 1 min and the mixture was allowed to warm to room temperature. After stirring for 20 h, the mixture was diluted with 75 mL of DCM and solid _NaHCO3 and Celite (2.0 g each) were carefully added to the vigorously stirred reaction mixture. The mixture was cooled to 0 °C and saturated aqueous _NaHCO3 (1.2 mL) was added dropwise to the vigorously stirred mixture. The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was filtered through a Celite pad and the pad was rinsed with DCM (30 mL). The combined filtrates were concentrated by rotary evaporation to give approximately 5 g of a crude orange oil. The crude was dissolved in DCM and automated flash chromatography on a Combiflash (80 g column, gradient 5 to 50% EtOAc in hexanes) afforded 399 (2.21 g, 83%) as a white flaky solid with 95% purity. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.17 (br s, 1H), 7.96 (d, 1H), 7.40-7.30 (m, 8H), 7.14-7.06 (m, 2H), 6.75 (d, J = 1.9 Hz, 1H), 5.45 (dd, J = 5.4 Hz, 2.0 Hz, 1H), 5.27 (dd, J = 8.3 Hz, 2.5 Hz, 1H), 4.76 (d, J = 12.4 Hz, 1H), 4.50 (d, J = 12.4 Hz, 1H), 4.33 (d, J = 10.6 Hz, 1H), 4.25-4.20 (m, 2H), 3.92 (d, J = 10.7 Hz, 1H), 3.61 (d, J = 10.7 Hz, 1H), 2.72 (s, 1H), 2.20 (s, 3H). ESI-MS: m/z 379.1 ([M-thiouridine] ⁺ ).

To a stirred solution of 399 (2.21 g, 4.36 mmol) in 1,4-dioxane (227 mL) and water (38 mL) at room temperature was added 1.0 M aqueous NaOH (38 mL, 38 mmol) all at once. The mixture was stirred at room temperature for 16 h and neutralized by dropwise addition of AcOH (2.17 mL, 38 mmol). The mixture was stirred for 30 min and then concentrated by rotary evaporation. The residue was partitioned between EtOAc and water (100 mL each). The organic layer was removed and the aqueous layer was extracted with EtOAc (1×100 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated by rotary evaporation to give 2.5 g of crude material. The crude was dissolved in DCM and automated flash chromatography on a Combiflash (80 g column, gradient 5 to 50% EtOAc in hexanes) afforded 400 (1.57 g, 77%) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.21 (br s, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.45-7.30 (m, 8H), 7.20-7.15 (m, 2H), 6.72 (d, J=2.5 Hz, 1H), 5.37 (dd, J=8.2 Hz, 2.3 Hz, 1H), 4.79 (d, J=11.9 Hz, 1H), 4.70 (d, J=11.9 Hz, 1H), 4.06 (d, J=11.9 Hz, 1H), 4.04 (d, J=11.9 Hz, 1H), 4.02 (d, J=11.9 Hz, 1H), 4.01 ...1 (d, J=11.9 Hz, 1H), 4.01 (d, J=11.9 Hz, 1H), 4.01 (d, J=11.9 Hz, 1H), z, 1H), 4.45 (d, J = 10.8 Hz, 1H), 4.41 (d, J = 10.8 Hz, 1H), 4.28 (td, J = 5.6 Hz, 2.6 Hz, 1H), 4.21 (d, J = 5.6 Hz, 1H), 3.95 (d, J = 10.6 Hz, 1H), 3.71 (d, J = 10.7 Hz, 1H), 3.08 (d J = 5.7 Hz, 1H), 2.77 (s, 1H). ESI-MS: m/z 465.1 ([M+H] ⁺ ).

To a stirred solution of 400 (1.57 g, 3.38 mmol) in DCM (68 mL) at −78° C. under nitrogen was added a 1.0 M solution of BCl ₃ in DCM (16.9 mL, 16.9 mmol) dropwise via syringe. The mixture was stirred at −78° C. for 3 h and then quenched by slow dropwise addition of a 7:10 v/v pyridine/MeOH mixture (68 mL). The mixture was allowed to warm to room temperature with stirring and concentrated by rotary evaporation to give 11 g of a crude oil. The crude was dissolved in 9:1 DCM:MeOH and bulk impurities were removed by automated flash chromatography on a Combiflash (120 g column, gradient 10 to 25% MeOH in DCM). Fractions containing the desired product were collected and concentrated to give 2 g of semi-pure product. The crude was dissolved in MeOH and immobilized on Celite. A second automated flash chromatography on a Combiflash (40 g column, gradient 2.5 to 25% MeOH in DCM) gave 401 (0.622 g, 65%) as a powdery white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.19 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 3.3 Hz, 1H), 5.95 (d, J = 8.1 Hz, 1H), 4.26 (d, J = 6.0 Hz, 1H), 4.23 (dd, J = 5.9 Hz, 3.4 Hz, 1H), 3.85 (d, J = 12.2 Hz, 1H), 3.77 (d, J = 12.2 Hz, 1H), 3.08 (s, 1H). ^13C NMR (100 MHz, _CD3OD ) δ 178.2, 162.3, 142.7, 106.9, 94.7, 85.6, 80.6, 79.2, 76.4, 71.0, 65.8. ESI-MS: m/z 285.0 ([M+H] ⁺ ).

[Example 139]

A stirred suspension of thiouracil (3.48 g, 27.2 mmol, 2.2 equiv) in HMDS (25.9 mL, 1 M) was heated to reflux under argon with 10 mg ammonium sulfate. After 2 h, the resulting clear solution was cooled and concentrated to give a white paste. A solution of the bromosugar (5.4 g, 12.35 mmol, 1 equiv) in DCE (40 mL) was then added via cannula to the flask of thiouracil with 2 x 10 mL DCE washes. The reaction was charged with mercuric oxide (3.48 g, 16 mmol, 1.3 equiv), mercuric bromide (3.56 g, 9.88 mmol, 0.8 equiv) was added, the reaction was fitted with a reflux condenser and brought to reflux. After 16 h, it was cooled and quenched with 100 mL of a 3:1 mixture of methanol and water. After stirring for 30 minutes, the reaction was diluted into 300 mL of water and extracted with dichloromethane (3 x 100 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction was purified by silica gel chromatography (2-10% methanol in dichloromethane) to give 2.5 g of the nucleoside as a mixture of two compounds with the exact masses. Further silica gel chromatography (20-70% ethyl acetate in hexanes) gave 785 mg of compound 404 (13%) and 805 mg of compound 405 (13%).

Compound 404 ¹ H NMR (400 MHz, chloroform-d) δ 8.03 (dd, J=34.2, 7.8 Hz, 4H), 7.86 (d, J=6.6 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.57-7.32 (m, 4H), 6.48 (d, J=21.7 Hz, 1H), 6.30 (d, J=6.6 Hz, 1H), 5.50 (dd, J=16.6, 8.1 Hz, 1H), 4.87-4.48 (m, 4H), 1.71 (d, J=21.5 Hz, 3H).

Compound 405 ¹ H NMR (400 MHz, chloroform-d) δ 8.06 (dd, J=26.3, 8.0 Hz, 5H), 7.86 (d, J=6.7 Hz, 1H), 7.71-7.33 (m, 7H), 6.43 (d, J=17.5 Hz, 1H), 6.29 (d, J=6.7 Hz, 1H), 5.69 (dd, J=21.8, 8.5 Hz, 1H), 4.94-4.35 (m, 5H), 1.66 (d, J=22.1 Hz, 3H).

A suspension of compound 404 (785 mg, 1.62 mmol) in 7M ammonia in methanol (16 mL, 0.1 M) was prepared. After 16 h, the reaction was concentrated and purified by silica gel chromatography (5-20% methanol in dcm) to give 220 mg of the diol (49%). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.85 (d, J=6.6 Hz, 1H), 6.38 (d, J=28.2 Hz, 1H), 6.19 (t, J=5.4 Hz, 1H), 4.13-3.91 (m, 2H), 3.85 (dd, J=12.6, 1.9 Hz, 1H), 3.64 (dd, J=12.5, 3.7 Hz, 1H), 1.62-1.42 (m, 3H). LCMS calculated _{for C10H13FN2O4S} 276.06 found 277.00 M+ ₁ ; 274.90 M- ₁

A suspension of compound 405 (805 mg, 1.62 mmol) in 7M ammonia in methanol (16 mL, 0.1 M) was prepared. After 16 h, the reaction was concentrated and purified by silica gel chromatography (5-20% methanol in dcm) to give 210 mg of the diol (46%). ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.89 (d, J=6.6 Hz, 1H), 6.43 (d, J=18.3 Hz, 1H), 6.19 (d, J=6.6 Hz, 1H), 4.02-3.88 (m, 1H), 3.81 (dd, J=12.5, 2.1 Hz, 1H), 3.72-3.53 (m, 1H), 3.39-3.23 (m, 1H), 1.56 (d, J=22.3 Hz, 3H). LCMS calculated for _{C10H13FN2O4S 276.06} found 274.90 M-1. The phosphoramidate prodrug _of compound 236 can be synthesized _using the general procedure of Example 93, and the triphosphate of compound 236 can be synthesized using the general procedure of Example 98.

[Example 140]

A stirred suspension of the nucleoside (190 mg, 0.73 mmol) in dichloromethane (14.6 mL, 0.05 M) was charged sequentially with DMAP (89 mg, 0.73 mmol), imidazole (124 mg, 1.83 mmol), and TBSCl (242 mg, 1.61 mmol) and stirred overnight. After 18 h, the reaction was concentrated, diluted in ether, and filtered. The solution was concentrated and purified by silica gel chromatography (5-50% ethyl acetate in hexanes) to give 200 mg (57%) of the desired bis-TBS nucleoside. ^1H NMR (400MHz, chloroform-d) δ 7.89 (d, J = 8.1 Hz, 1H), 6.18 (d, J = 17.8 Hz, 1H), 5.70 (d, J = 8.1 Hz, 1H), 4.17-3.90 (m, 3H), 3.87-3.64 (m, 1H), 1.31 (d, J = 21.7 Hz, 3H), 0.90 (d, J = 10.2 Hz, 18H), 0.10 (s, 12H).

A stirred solution of 408 (200 mg, 0.409 mmol) in DCM (4 mL) was charged with DMAP (100 mg, 0.818 mmol) and triethylamine (120 μl, 0.859 mmol). The clear solution was cooled to 0 °C and then charged with 2,4,6-triisopropylbenzene-1-sulfonyl chloride (248 mg, 0.818 mmol). The reaction was stirred for 18 h and then cooled back to 0 °C. A 0 °C solution of 2,6-dimethylphenol (150 mg, 1.228 mmol), DABCO (9.18 mg, 0.082 mmol) and triethylamine (171 μl, 1.228 mmol) in DCM (4 mL) was prepared and added dropwise to the reaction. The reaction was stirred for 3 h and then quenched with cold 50 mL of saturated NaHCO ₃ and 100 mL of DCM. The separated organic layer was washed once with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo The resulting oil was purified with 5-50% EtOAc in hexanes to give 234 mg of the phenol ether as a glass. ^1H NMR (400MHz, chloroform-d) δ 8.33 (d, J = 7.4 Hz, 1H), 7.04 (s, 3H), 6.33 (d, J = 17.8 Hz, 1H), 6.08 (d, J = 7.4 Hz, 1H), 4.30-3.94 (m, 3H), 3.84 (d, J = 12.0 Hz, 1H), 2.13 (s, 6H), 1.32 (d, J = 21.8 Hz, 3H), 0.95 (d, J = 27.3 Hz, 18H), 0.15 (d, J = 15.3 Hz, 12H).

A stirred solution of 409 (200 mg, 0.338 mmol) in toluene (6.6 mL, 0.05 M) was charged with Lawesson's reagent (204 mg, 0.506 mmol) and heated to 110° C. After 3 h, the reaction was cooled, concentrated onto 1 g of Celite, and purified by silica gel chromatography (1-20% EtOAc/Hexanes) to give a total of 200 mg of material containing a small amount of phosphorus impurity, which was carried over. ^1H NMR (400MHz, chloroform-d) δ 8.42 (d, J = 7.4 Hz, 1H), 7.41 (d, J = 18.2 Hz, 1H), 7.03 (s, 3H), 6.28 (d, J = 7.4 Hz, 1H), 4.34-3.95 (m, 4H), 2.11 (s, 6H), 1.44 (d, J = 21.6 Hz, 3H), 1.06-0.82 (m, 18H), 0.14 (dd, J = 9.0, 1.1 Hz, 12H).

To a stirred solution of 410 (200 mg, approx. 0.338 mmol) in THF (6.6 mL, 0.5 M) was charged TBAF (821 uL, 1 M in THF, 0.821 mmol). The reaction was stirred for 18 h, concentrated onto 1 g of Celite, then purified by silica gel chromatography (2-7% methanol in DCM) to give 100 mg (approx. 80%, 2 steps) of material containing a small amount of tetrabutylammonium salt. ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.75 (dd, J=7.5, 1.7 Hz, 1H), 7.35 (dd, J=18.2, 1.7 Hz, 1H), 7.22-6.96 (m, 3H), 6.60-6.41 (m, 1H), 4.13-3.91 (m, 3H), 3.91-3.73 (m, 2H), 2.11 (s, 6H), 1.42 (dd, J=22.2, 1.6 Hz, 3H).

A solution of syn-o-nitrobenzaldoxime (131 mg, 0.789 mmol) in acetonitrile (2.6 mL) was charged with 1,1,3,3-tetramethylguanidine (99 μl, 0.789 mmol) to give an orange solution. After 15 min, the resulting solution was added dropwise to a stirred solution of 411 (100 mg, 0.63 mmol) in acetonitrile (2.6 mL). After 3 h, the reaction was concentrated onto 500 mg of Celite and purified by silica gel chromatography (2-20% methanol in DCM) to give 45 mg of 412, 62%. ^1H NMR (400 MHz, methanol- _d4 ) δ 8.17 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 18.7 Hz, 1H), 5.98 (d, J = 8.1 Hz, 1H), 4.09-3.87 (m, 3H), 3.80 (dd, J = 12.5, 1.9 _Hz , 1H), 1.43 (d, J = _{22.2 Hz} , 3H). MS _C10H13FN2O4S [M-H ⁺ ]; calculated: 277.1, found: 277.0.

The triphosphate of compound 412 has activity against dengue virus infection.

[Example 141]
5'-Phosphoramidate prodrugs synthesized using a general procedure:

[Example 142]
Synthesis of 2'-methyl-2-selenouridine:

Synthesis of 421 (2R,3R,5R)-5-((benzoyloxy)methyl)-3-methyl-2-(4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3,4-diyldibenzoate. To a stirred solution of 420 (2.899 g, 4.94 mmol) in anhydrous CH ₂ Cl ₂ (35 ml) was added iodomethane (3.08 ml, 49.4 mmol) and cooled to 0° C. Then DBU (1.106 ml, 7.41 mmol) was added dropwise and stirred at 0° C. for 1 h. The reaction was quenched by addition of 15 mL of water and extracted with CH ₂ Cl _2. The aqueous layer was separated, the organic layer was washed with water (2×15 mL) and the aqueous layer was back extracted with CH ₂ Cl ₂ (25 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give an oil which was purified by silica gel column chromatography using a linear gradient of 0-50% EtOAC in hexanes to give pure 421 as a white solid (2.678 g, 90% yield). ^1H NMR (400MHz, chloroform-d) δ 8.11-7.98 (m, 4H), 7.83-7.79 (m, 2H), 7.67 (d, J=7.9 Hz, 1H), 7.65-7.53 (m, 2H), 7.53-7.32 (m, 5H), 7.32-7.16 (m, 2H), 6.63 (s, 1H), 5.95 (dd, J=7.8, 0.6 Hz, 1H), 5.64 (d, J=6.0 Hz, 1H), 5.00-4.63 (m, 3H), 2.63 (s, 3H), 1.68 (s, 3H). 13C NMR (100 MHz, _CDCl3 ) δ 167.7, 166.2, 165.5, 165.3, 162.9, 138.5, 134.0, 133.9, 130.1, 129.9, 129.8, 129.6, 129.4, 129.3, 128.9, 128.8, 128.6, 128.4, 109.6, 91.21, 85.5, 80.5, 77.5, 77.2, 76.9, 74.7, 62.6, 19.4, 15.4.

Synthesis of 422 Absolute ethanol (10 ml) was cooled to 0° C. and deoxygenated by bubbling argon through for 15 min, and the solution was added to a mixture of grey powdered selenium (0.263 g, 3.33 mmol) and sodium tetrahydroborate (0.132 g, 3.50 mmol) cooled in an ice bath. After stirring for 30 min, the solution was carefully added to the deoxygenated neat solid of 421 (1.000 g, 1.665 mmol) at 0° C. and stirred for 10 min at 0° C., then warmed to room temperature overnight. TLC (5% MeOH:CH ₂ Cl ₂ ) showed the product R _f =0.71. The mixture was bubbled with argon for 1 h to remove H ₂ Se, diluted with EtOAC (30 mL), washed with water (15 mL), followed by brine (15 mL). The aqueous layer was re-extracted with EtOAc (30 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give a crude solid which was purified by silica column chromatography using a 0-10% linear gradient of methanol in dichloromethane to give 422 as a pale yellow solid. The solid was re-purified by column chromatography using EtOAc and hexanes to remove minor impurities and give pure 422 in 99% yield. ^1H NMR (300MHz, chloroform-d) δ 10.25 (s, 1H), 8.07 (t, J = 8.4 Hz, 4H), 7.81 (d, J = 6.0 Hz, 2H), 7.77 (s, 1H), 7.71 (d, J = 6.0 Hz, 1H), 7.67-7.36 (m, 7H), 7.30-7.19 (m, 2H), 5.96 (d, J = 8.3 Hz, 1H), 5.61 (d, J = 6.0 Hz, 1H), 5.01-4.59 (m, 3H), 1.77 (s, 3H).

Synthesis of 423 A solution of 422 (0.950 g, 1.500 mmol) in 7N NH ₃ in methanol (10 mL) was heated in a sealed tube at 40° C. overnight. TLC (10% MeOH:CH ₂ Cl ₂ ) showed complete conversion with product R _f =0.2 and starting material R _f =0.7. The reaction mixture was concentrated and the resulting crude mixture was purified by silica gel column chromatography eluting with a 0-20% linear gradient of methanol in CH ₂ Cl ₂ to afford 423 as a pale yellow solid (0.350 g, 72.7% yield). ^1H NMR (300MHz, methanol d4) δ 8.29 (d, J=8.1 Hz, 1H), 7.10 (s, 1H), 6.08 (d, J=8.1 Hz, 1H), 4.62 (s, 1H), 4.08-3.69 (m, 4H), 1.28 (s, 3H); ^13C NMR (150MHz, DMSO): 179.3, 161.76, 143.8, 111.1, 100.5, 85.4, 81.8, 74.5, _{61.4, 23.5;HRMS [M+Na]+ calculated for C10H14N2O5NaSe : 344.99601} ^, _found : 344.99632.

[Example 143]
5'-Phosphoramidate prodrugs synthesized using a general procedure:

[Example 144]
5'-Triphosphates synthesized using the general procedure:

[Example 145]
Synthesis of 2'-methyl-4-thiouridine-5'-monophosphate:

To a 10 mL flame dried pear shaped flask containing 1-((2R,3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-4-thioxo-3,4-dihydropyrimidin- ₂ (1H)-one (0.205 g, 0.747 mmol) was added PO(OMe) (1.868 mL) to give a light yellow solution. This was cooled to 0° C. and then _POCl (0.139 mL, 1.495 mmol) was added dropwise to give a still light yellow solution. After stirring at 0° C. for 4.5 hours, TLC showed no starting material. The crude mixture was poured into 30 mL of cold DI water. After stirring for 5 minutes, it was transferred to a separatory funnel and _CHCl (30 mL) was added. The aqueous layer was washed once more with _CHCl (30 mL). The aqueous layer was then neutralized to approximately pH=7.2 by dropwise addition of concentrated NH ₄ OH. The mixture was re-extracted once with CHCl ₃ (30 mL). The aqueous layer was concentrated in vacuo to give a light yellow solid. The solid was stirred with MeOH (60 mL) for 1 hour, which was then filtered through sintered glass. The filtrate was treated with Celite and concentrated in vacuo. The crude material was purified by SiO ₂ column chromatography eluting with 100% DCM to 100% IPA, then IPA/NH ₄ OH/H ₂ O=8/1/1 to 7/2/1 to give the product and some other inorganics (white). The material was then diluted with MeOH and Celite was added. The crude material was concentrated in vacuo and purified with 100% IPA to IPA/NH ₄ OH/H ₂ O=9/1/1 to 8/1/1 to 7/2/1. The product containing fractions were combined, concentrated in vacuo and co-evaporated with MeOH to give a yellow oil which was dissolved in water and lyophilized overnight to give 427 (25 mg) as a yellow solid.
^1H NMR (400MHz, _CD3OD ); δ 7.99 (d, J=8.0 Hz, 1H), 6.51 (d, J=7.6 Hz, 1H), 5.93 (s, 1H), 4.29-4.25 (m, 1H), 4.14-4.09 (m, 1H), 4.03-3.94 (m, 2H), 1.18 (s, 3H). ^13C NMR (100 MHz, _CD3OD ); δ 192.3, 150.2, 136.7, 114.8, 93.2, 83.1, 80.3, 73.0, 63.3, 20.3. ^31P NMR (400MHz, _CD3OD ); δ 1.27. HRMS (ESI ₎ calculated for _C10H14O8N2PS [ _{M -} H] ⁺ : 353.0214. Found: 353.0213.

[Example 146]
Synthesis of 2'-methyl-4-thiouridine-5'-diphosphate:

To a stirred solution of 427 (39 mg, 110 umol) in DMF (1.1 mL, 0.1 M) was charged with tributylamine (262 uL, 1.1 mmol). The reaction was stirred for 25 min then concentrated in vacuo. The resulting paste was redissolved in DMF (1.1 mL, 0.1 M) and charged with carbonyldiimidazole (89 mg, 550 umol) to give a clear solution. After stirring for 24 h, methanol (150 uL, 1.4 mmol) was added dropwise. After 2 h the reaction was charged with tributylammonium phosphate (12 mL, 0.5 M in DMF, 2.2 mmol) to give a cloudy solution. The reaction was stirred for 2 h then the solvent was removed and the crude paste was loaded onto a DEAE column eluting from 50-450 mM TEAB to give the triethylammonium salt of the diphosphate. The diphosphate was converted to the sodium salt by elution through a column of Na ⁺ Dowex at 0° C. to give 28 mg, 51% yield of the sodium salt of the diphosphate.
^1H NMR (400MHz, _D2O ) 57.73 (d, J = 7.6 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 5.87 (s, 1H), 4.24-4.11 (m, 2H), 4.00 (d, J = 2.1 Hz, 2H), 1.08 (s, 3H). ^32P NMR (162MHz, _D2O ) -6.55 (d, J = 23.0 Hz ₎ , -11.02 (d, J = 22.9 _Hz ) _{. HRMS C10H16N2O11P2S [} ^M- ]; calculated: 432.995, found: 432.988.

[Example 147]

2-Thiouracil (1.025 g, 8.0 mmol) was persilylated by mixing with ammonium sulfate (0.053 g, 0.400 mmol) in hexamethyldisilazane (16.77 mL, 80.0 mmol) and heating the mixture to reflux for 16 h. The resulting pale blue solution was cooled to room temperature and the volatiles were removed by rotary evaporation followed by high vacuum to give the persilylated 2-thiouracil as a pale blue liquid that was >95% pure by ¹ H NMR analysis. The entire material was used immediately in the next step.

To a stirred solution of crude freshly prepared persilyl-2-thiouracil (8.0 mmol) in 1,2-dichloroethane (20.0 mL) at room temperature under nitrogen was added a solution of 429 (1.666 g, 4.00 mmol) in 1,2-dichloroethane all at once. The stirred solution was cooled to 0° C. and SnCl ₄ (0.94 mL, 8.00 mmol) was added dropwise via syringe. The mixture was allowed to warm to room temperature and stirred overnight for 16 h. The mixture was then recooled to 0° C. and carefully quenched with saturated aqueous NaHCO ₃ (40 mL). The mixture was allowed to warm to room temperature and stirred vigorously for 1 h. The mixture was extracted with EtOAc (2×150 mL) and the combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated by rotary evaporation to give 3.5 g of crude residue. The crude residue was dissolved in DCM and purified by automated flash chromatography on a Combiflash (80 g column, gradient 5 to 50% EtOAc in hexanes) to give 430 (0.708 g, 1.46 mmol, 37% yield) as a white flaky solid. ¹ H NMR analysis showed approximately 95% purity; the entire compound was used directly in the next step. ^1H NMR (400MHz, _CDCl3 ) δ 9.52 (br s, 1H), 8.18 (d, J = 7.0Hz, 2H), 8.06 (d, J = 7.0Hz, 2H), 7.67-7.57 (m, 2H), 7.59 (d, J = 8.3Hz, 1H), 7.55-7.45 (m, 5H), 5.96 (dd, J = 8.3Hz, 2.1Hz, 1H), 5.33 (dd, J = 52.0Hz, 2.4Hz, 1H), 4.84-4.68 (m, 3H), 1.65 (d, J = 2.0Hz, 3H).

A sealable pressure tube was charged with a stir bar, 430 (0.708 g, 1.461 mmol) and 7N ammonia solution in MeOH (20 mL, 140 mmol) at 0° C. The tube was sealed, warmed to room temperature and stirred at room temperature for 3 days. The tube was then heated at 45° C. for 5 h, recooled to room temperature and concentrated by rotary evaporation to give 700 mg of crude. The crude was dissolved in MeOH and immobilized on Celite. Automated flash chromatography on a Combiflash (24 g column, gradient 0 to 10% MeOH in DCM) gave approximately 450 mg of the partially deprotected 2′-monobenzoate product. This compound was charged in a sealable pressure tube with a stir bar and 7N ammonia solution in MeOH (20 mL, 140 mmol). The mixture was heated with stirring, with the heat gradually increased, until the reaction was complete: 45° C. for 24 h, 55° C. for 24 h, and finally 75° C. for 24 h. The mixture was cooled to room temperature and concentrated by rotary evaporation to give 500 mg of a brown oil. The crude was dissolved in MeOH and immobilized on Celite. Automated flash chromatography on a Combiflash (24 g column, gradient 0 to 10% MeOH in DCM) gave 160 mg of almost pure compound, which was again dissolved in MeOH and immobilized on Celite. A second automated flash column on a Combiflash (12 g column, gradient 0 to 7% MeOH in DCM) gave 115 mg of a white solid with some solvent occlusion. The solid was dissolved in water, frozen in a dry ice/acetone bath, and lyophilized to give 431 (0.102 g, 0.369 mmol, 9.2% yield over two steps) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.70 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 6.02 (d, J = 8.2 Hz, 1H), 5.86 (s, 1H), 5.47 (t, J = 4.9 Hz, 1H), 4.76 (dd, J = 52.9 Hz, 8.7 Hz, 1H), 4.20-4.10 (br m, 1H), 3.85 (ddd, J = 13.1 Hz, 5.4 Hz, 2.1 ^Hz , 1H), 3.66 (ddd, J = 12.8 Hz, 4.9 _Hz , 2.5 Hz, 1H), 1.20 (s, 3H); 13C NMR (100MHz, D2O) δ 7.94 (d, J = 8.2Hz, 1H), 6.98 (d, J = 2.1Hz, 1H), 6.17 (d, J = 8.2Hz, 1H), 4.81 (dd, J = 52.4, 8.1Hz, 1H), 4.38-4.27 (m, 1H), 4.04 (dd, J = 13.2Hz, 2.7Hz, 1H), 3.90 (dd, J = 13.2Hz, 3.6Hz, 1H), 1.34 (s, 3H); ^13C NMR (100MHz, _D2O ) δ 176.5, 162.2, 141.8, 106.9, 94.2 (d,J=3.8 Hz), 91.3 (d,J=190.6 Hz), 79.9 (d,J=24.3 Hz), 78.6 (d,J=14.2 Hz), 59.0, 19.5; ¹⁹ F NMR (376 MHz, D ₂ O) δ-212.37 (dd,J=52.3 Hz, 14.3 Hz); HRMS calculated for C ₁₀ H ₁₃ FN ₂ O ₄ SNa [M+Na] ⁺ : 299.04723, found: 299.04743.

[Example 148]

3,5-di-O-benzyl-4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose:
To a solution of 3-O-benzyl-4-C-hydroxymethyl-1,2-O-isopropylidene-α-D-ribofuranose (10.0 g, 32.2 mmol) in anhydrous DMF (50 mL) at −5° C. was added a suspension of NaH (60% (w/w) in mineral oil, total of 1.48 g, 37.1 mmol in two portions during 30 min). Benzyl bromide (4.4 mL, 37.1 mmol) was added dropwise and stirring at room temperature was continued for 3 h, then ice-cold water (50 mL) was added. The mixture was extracted with EtOAc (4×50 mL) and the combined organic phase was dried (Na ₂ SO ₄ ). After evaporation, the residue was purified by silica gel column chromatography eluting with 15-20% EtOAc in hexane (v/v) to give the product, 433 (8.84 g, 69%) as a colorless liquid. ^1H NMR (400MHz, _CDCl3 ); δ 7.37-7.25 (m, 10H), 5.79 (d, J = 4.0Hz, 1H), 4.79 (d, J = 12.0Hz, 1H), 4.65 (t, J = 4.8Hz, 1H), 4.54 (d, J = 12.0Hz, 1H), 4.51 (d, J = 12.0Hz, 1H), 4.46 (d, J = 12.0Hz, 1H), 4.27 (d, J = 4.8Hz, 1H), 3.93 (d, J = 12.0Hz, 1H), 3.83 (d, J = 12.0Hz, 1H), 3.61 (d, J = 12.0Hz, 1H), 3.54 (d, J = 12.0Hz, 1H), 2.26 (br s, 1H), 1.64 (s, 3H), 1.35 (s, 3H).

3,5-di-O-benzyl-4-C-fluoromethyl-1,2-O-isopropylidene-α-D-ribofuranose:
To _a stirred solution of 433 (7.87 g, 19.65 mmol) in _CH2Cl2 (190 mL) were added pyridine (2.37 mL, 29.5 mmol) and trifluoromethanesulfonic anhydride (3.64 mL, 21.62 mmol) successively at 0°C. The reaction mixture was stirred at 0°C for about 45 min, then TLC showed completion of the reaction to a single faster moving compound, after which the mixture was washed with water and _brine . The combined aqueous layers were back-extracted with _CH2Cl2 . The combined organic phases _were dried ( _Na2SO4 ) and concentrated under reduced pressure to give a light brown solid.

The solid from the previous step was dissolved in acetonitrile (100 ml). A 1 M solution of tetrabutylammonium fluoride in THF (78 mL, 78.0 mmol) was added and the reaction mixture was stirred at about 50° C. overnight. Removal of the solvent under reduced pressure and silica gel chromatography of the dark oily residue [10-15% EtOAc in hexanes] afforded 434 (4.3 g, 55%) as a colorless oil. ^1H NMR (400MHz, _CDCl3 ); δ 7.34-7.26 (m, 10H), 5.77 (d, J = 3.6 Hz, 1H), 4.87 (dd, J = 10.0, 48.8 Hz, 1H), 4.73 (d, J = 10 Hz, 1H), 4.63-4.47 (m, 5H), 4.26 (dd, J = 1.6, 4.8 Hz, 1H), 3.61 (dd, J = 1.6, 10.4 Hz, 1H), 3.55 (dd, J = 1.6, 10.4 Hz, 1H), 1.63 (s, 3H), 1.35 (s, 3H). ^19F NMR (400MHz, _CDCl3 ); δ -28.46 (t, J = 48.8 Hz).

1,2-di-O-acetyl-3,5-di-O-benzyl-4-C-fluoromethyl-D-ribofuranose:
A stirred solution of 434 in 70% acetic acid (73 mL) was charged with TFA (7.3 mL) and heated to 40° C. After 4 h, the reaction was concentrated and coevaporated with toluene. The paste was then dissolved in pyridine (27 mL) and charged with acetic anhydride (10.57 mL, 112 mmol). After stirring overnight, the reaction was concentrated, taken up in ethyl acetate and washed with water. The dryness (Na ₂ SO ₄ ) was filtered and concentrated to give an oil which was purified by silica gel chromatography (5-20% ethyl acetate in hexanes) to give 435 (3.54 g, 71%) as a colorless liquid. ^1H NMR (400MHz, _CDCl3 ); δ 7.35-7.25 (m, 10H), 6.18 (s, 1H), 5.35 (d, J=5.2 Hz, 1H), 4.73-4.66 (m, 1H), 4.60-4.48 (m, 5H), 4.43 (d, J=4.8 Hz, 1H), 3.68 (dd, J=1.6, 10.4 Hz, 1H), 3.51 (dd, J=1.6, 10.4 Hz, 1H), 2.11 (s, 3H), 1.90 (s, 3H).

1-(2'-O-acetyl-3',5'-di-O-benzyl-4'-C-fluoromethyl-β-D-ribofuranosyl)2-thiouracil:
A stirred mixture of 2-thiouracil (600 mg, 4.68 mmol) and ammonium sulfate (30 mg, 0.23 mmol) in hexamethyldisilazane (4.9 mL, 23.41 mmol) and chlorobenzene (10 mL) was heated to reflux under nitrogen for 3-4 hours until all solids had dissolved and a pale blue solution had formed. The mixture was cooled to room temperature and concentrated by rotary evaporation followed by high vacuum to give a blue liquid with some white solids inside. The entire crude material was carried on immediately to the next step.

To a cloudy stirred solution of 435 (950 mg, 2.13 mmol) and bis-silylated 2-thiouracil in 1,2-DCE (10.0 ml) at 0 °C under nitrogen, tin(IV) chloride (0.5 ml, 4.26 mmol) was added. The mixture immediately turned yellow and became less cloudy. The mixture was allowed to warm to room temperature and stirred overnight. After stirring at room temperature for 15 h, the mixture was diluted with 25 mL of DCM and 1.0 g each of solid _NaHCO3 and Celite were carefully added to the vigorously stirred reaction mixture. The mixture was cooled to 0 °C and saturated aqueous _NaHCO3 (2 mL) was added dropwise with vigorously stirring. The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was filtered through a small Celite pad, which was then rinsed with DCM (20 mL). The combined filtrate was concentrated to give an oil, which was purified by silica gel chromatography (30-35% ethyl acetate in hexanes) to afford 436 (890 mg, 81%) as a colorless foamy solid. ^1H NMR (400MHz, _CDCl3 ); δ 10.11 (br s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.40-7.19 (m, 10H), 6.81 (d, J = 2.8 Hz, 1H), 5.49 (dd, J = 3.2, 4.8 Hz, 1H), 5.38 (d, J = 8.0 Hz, 1H), 4.73-4.59 (m, 3H), 4.50-4.35 (m, 4H), 3.95 (d, J = 10.0 Hz, 1H), 3.57 (d, J = 10.4 Hz, 1H), 2.15 (s, 3H). ^19F NMR (400MHz, _CDCl3 ); δ -28.22 (t, J = 50.8 Hz).

1-(3',5'-di-O-benzyl-4'-C-fluoromethyl-β-D-ribofuranosyl)2-thiouracil:
To a stirred solution of 436 (890 mg, 1.73 mmol) in methanol (29 ml) at 0° C. was added methanolic ammonia (6.2 mL, 7 M in MeOH). The mixture was warmed to 40° C. and stirred overnight. The solvent was evaporated under reduced pressure and then purified by silica gel chromatography (25-30% ethyl acetate in hexanes) to give 437 (800 mg, 89%) as a colorless foamy solid.

1-(4'-C-fluoromethyl-β-D-ribopentofuranosyl)2-thiouracil:
To a 50 mL pear-shaped flask containing 437 (800 mg, 1.693 mmol) was added dry DCM (20.0 mL) under _N2 . It was cooled to -78 °C and then _BCl3 (11.8 mL, 11.8 mmol, 1.0 M in DCM) was added dropwise. The reaction was stirred at -78 °C for 15 min and then slowly warmed to -40 °C, TLC showed no starting material, then MeOH (5 mL) was added dropwise and stirred at -40 °C. The solvent was then removed in vacuo and the crude material was purified by _SiO2 column chromatography eluting with 5-7% MeOH in DCM to give 438 (340 mg, 69%) as a white solid. ^1H NMR (400MHz, _CD3OD ); δ 8.21 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 5.6 Hz, 1H), 5.98 (d, J = 8.0 Hz, 1H), 4.67 (d, J = 0.8 Hz, 1H), 4.56 (d, J = 2.0 Hz, 1H), 4.34-4.30 (m, 2H), 3.81-3.78 (m, 2H). ^13C NMR (100 MHz, _CD3OD ); δ 178.9, 162.4, 143.0, 107.3, 93.3, 88.9, 88.8, 85.3, 83.6, 76.7, 72.3, 63.5. ^19F NMR (400 MHz, _CDCl3 ); δ -30.18 (t, J = 50.8 _{Hz )} . _HRMS (ESI) calculated for _{C10H13O5N2FNaS} [M+Na] ⁺ : 315.0421. Found: 315.0424.

[Example 149]

To a 100 mL pear-shaped flask containing 260 (300 mg, 0.552 mmol) was added _H2O (8.00 ml) and _Et3N (8 ml). It was heated to 35°C (oil bath temperature). Started at 4:50 pm and stopped at 9 am. After stirring overnight, TLC showed no starting material. The solvent was then removed in vacuo, then Celite was added and the mixture was concentrated in vacuo. The crude material was purified by _SiO2 column chromatography eluting with iPrOH (3 CV) to iPrOH/ _NH4OH /H2O = 8/1/1 to give 439 (0.18 g, 77% yield) as a yellow solid.
^1H NMR (400MHz, _D2O ); δ 7.91 (d, J = 7.6Hz, 1H), 6.66 (d, J = 7.6Hz, 1H), 5.98 (s, 1H), 4.23-4.11 (m, 2H), 4.03-3.96 (m, 2H), 3.62-3.55 (m, 1H), 1.29 (d, J = 6.8Hz, 3H), 1.21 (s, 3H). ^13C NMR (100MHz, _D2O ); δ 190.4, 180.4, 149.0, 136.2, 113.7, 91.7, 80.7, 79.0, 71.6, 61.9, 51.0, 20.4, 18.8. ^31P NMR (400 MHz, _D2O ); δ 7.67. _HRMS (ESI) calculated ^{for C13H19O9N3PS[M-H]+} _{: 424.0585} . Found _: 424.0584.

[Example 150]

To a 250 mL pear-shaped flask containing 1-((2R,3R,4S,5R)-5-azido-3,4-bis((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (6.4 g, 10.19 mmol) under argon was added dry DCM (85 ml) to give a colourless solution. This was treated with N,N-dimethylpyridin-4-amine (2.490 g, 20.38 mmol) and triethylamine (2.98 ml, 21.40 mmol) to give a still colourless solution. The flask was cooled to 0° C. and then 2,4,6-triisopropylbenzene-1-sulfonyl chloride (6.17 g, 20.38 mmol) was added. After 1 h the ice-water bath was removed. After stirring for 17 hours, the reaction became a brownish solution. It was cooled to 0°C and then a solution of 2,6-dimethylphenol (3.73 g, 30.6 mmol), DABCO (0.229 g, 2.038 mmol) and triethylamine (4.26 ml, 30.6 mmol) in dry DCM (21.23 ml) was added dropwise. After addition, the ice-water bath was removed. After stirring for 5 hours, it was quenched with 50 mL NaHCO ₃ and the organic layer was separated and washed again once with 50 mL water and once with 50 mL brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was dissolved in DCM and purified by ISCO column chromatography (120 g, 50 mL each) eluting with 100% to 20% EtOAc in hexanes in 30 min (product emerged at approximately 4.5% EtOAc in hexanes) to give the product, which was triturated with hexanes to give 441 (4.7 g, 6.42 mmol, 63.0% yield) as a white solid.
^1H NMR (400MHz, _CDCl3 ) δ 8.28 (d, J = 7.4 Hz, 1H), 7.04 (d, J = 1.6 Hz, 3H), 6.14 (d, J = 3.7 Hz, 1H), 6.10 (d, J = 7.4 Hz, 1H), 4.37-4.29 (m, 1H), 4.26 (d, J = 4.7 Hz, 1H), 3.86 (d, J = 11.3 Hz, 1H), 3.64 (d, J = 11.3 Hz, 1H), 2.14 (s, 6H), 0.99 (s, 8H), 0.96 (s, 8H), 0.92 (s, 8H), 0.18 (d, J = 7.1 Hz, 6H), 0.14 (d, J = 3.1 Hz, 6H), 0.08 (d, J = 0.5 Hz, 5H).

To a 500 mL round bottom flask (rbf) containing 441 (12.7 g, 17.35 mmol) was added dry toluene (173 ml) under argon. 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (10.52 g, 26.0 mmol) was then added. The mixture was heated to 110° C. for 5 h, the crude material was concentrated in vacuo, and the crude material was purified by SiO ₂ column chromatography eluting with 100% hexanes to 5% EtOAc in hexanes to 10% EtOAc in hexanes to give 442 (10 g, 13.37 mmol, 77% yield) as a glassy solid which contained some impurity but was used directly in the next step.

To a 200 mL pear-shaped flask containing 442 (0.14 g, 0.187 mmol) (yellow solid), dry THF (1.871 ml) was added to give a yellow solution. It was evacuated and backfilled with argon. The flask was cooled to 0° C., then TBAF (0.599 ml, 0.599 mmol) was added dropwise, followed by glacial AcOH (0.034 ml, 0.599 mmol). After 3 min, the ice-water bath was removed. After 1.5 h, TLC showed no starting material. The crude mixture was then diluted with CHCl ₃ , which was poured into a separatory funnel. Saturated NaHCO ₃ was then added. The aqueous layer was re-extracted once with CHCl ₃ , and the combined organic layers were washed once with brine. Again, the aqueous layer was re-extracted with DCM. The combined organic layers were dried (Na ₂ SO ₄ ), filtered, and concentrated in vacuo. The crude material was purified by _SiO2 column chromatography eluting with 100% DCM (75 mL, 3 CV) to 1% MeOH in DCM (100 mL) to 2% MeOH in DCM (200 mL) to afford 443 (70 mg, 0.173 mmol, 92% yield) as an off-white solid.
^1H NMR (400MHz, _CDCl3 ) δ 8.54 (d, J = 7.2 Hz, 1H), 7.9 (s, 3H), 6.60 (s, 1H), 6.39 (d, J = 7.6 Hz, 1H), 4.39-4.26 (m, 3H), 4.05-3.90 (m, 2H), 3.16 (d, J = 8.8 Hz, 1H), 2.14 (s, 6H).

To a 10 mL pear-shaped flask containing 443 (70 mg, 0.173 mmol) was added dry CH ₃ CN (1.7 mL) to give a light yellow solution. Then to another 10 mL flask containing syn-o-nitrobenzaldoxime (86 mg, 0.518 mmol) was added dry CH ₃ CN (1.7 mL) followed by 1,1,3,3-tetramethylguanidine (0.065 mL, 0.518 mmol) to give an orange solution. This was added dropwise to the previous flask to finally give an orange solution. After stirring at room temperature for 2 hours, TLC showed no starting material. Silica gel was then added and the crude material was concentrated in vacuo. The crude material was purified by SiO ₂ column chromatography eluting with 5% MeOH in DCM to 7.5% MeOH in DCM to give 444 (38 mg, 73% yield) as an off-white solid.
^1H NMR (400 MHz, _CD3OD ) δ 8.20 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 4.0 Hz, 1H), 5.97 (d, J = 8.4 Hz, 1H), 4.34-4.27 (m, 2H), 3.68 (dd, J = 38.4, 12.0 Hz, 2H) ^.13C NMR (100 _MHz , CD3OD ₎ ; δ 178.5 _, 162.4, 142.4, 107.3, 101.1, 95.2, 75.8, 72.4, 64.2.HRMS (ESI) calculated for _C9H11O5N5NaS [M+Na] ⁺ : _324.0373 . Actual value: 324.0370.

[Example 151]
5'-Phosphoramidate prodrugs synthesized using a general procedure:

[Example 152]
Assay Protocol (1) Screening Assays for DENV, JEV, POWV, WNV, YFV, PTV, RVFV, CHIKV, EEEV, VEEV, WEEV, TCRV, PCV, JUNV, MPRLV Primary Cytopathic Effect (CPE) Reduction Assay. A four-concentration CPE inhibition assay is performed. Confluent or near-confluent cell culture monolayers are prepared in 96-well disposable microplates. Cells are maintained in MEM or DMEM supplemented with FBS as required for each cell line. For antiviral assays, the same medium is used but FBS is reduced to 2% or less and supplemented with 50 μg/ml gentamicin. Test compounds are prepared at four log ₁₀ final concentrations, usually 0.1, 1.0, 10 and 100 μg/ml or μM. Virus and cell control wells are on every microplate. In parallel, a known active drug is tested as a positive control drug using the same method applied for the test compound. The positive control is tested with each test run. The assay is started by first removing the growth medium from the 96-well plate of cells. The test compound is then applied to the wells at 2X concentration in a volume of 0.1 ml. Virus is placed in those wells designated for virus infection, usually in a volume of 0.1 ml with a 50% cell culture infectious dose (CCID ₅₀ ) of <100. Virus-free medium is placed in the toxicity control wells and cell control wells. Virus control wells are treated similarly with virus. The plate is incubated at 37° C. with 5% CO ₂ until maximum CPE is observed in the virus control wells. The plate is then stained with 0.011% neutral red for approximately 2 hours in a 37° C. with 5% CO ₂ incubator. The neutral red medium is removed by complete aspiration, and the cells can be rinsed 1X with phosphate buffered saline (PBS) to remove residual dye. The PBS is completely removed and the incorporated neutral red is eluted with 50% Sorensen citrate buffer/50% ethanol (pH 4.2) for at least 30 minutes. The neutral red dye penetrates into viable cells, therefore the more intense the red color, the greater the number of viable cells present in the well. The dye content in each well is quantified using a 96-well spectrophotometer at a wavelength of 540 nm. Using a Microsoft Excel computer-based spreadsheet, the dye content in each set of wells is converted to a percentage of the dye present in untreated control wells. The 50% effective ( _EC50 , virus inhibitory) and 50% cytotoxic ( _CC50 , cell inhibitory) concentrations are then calculated by linear regression analysis. The quotient of _CC50 divided by _EC50 indicates the selectivity index (SI) value.

Secondary CPE/Viral Yield Reduction (VYR) Assay. This assay involves a similar methodology to that described in the previous paragraph using 96-well microplates of cells. Differences are noted in this section. Eight half-log ₁₀ concentrations of inhibitors are tested for antiviral activity and cytotoxicity. After sufficient viral replication has occurred, a sample of the supernatant is taken from each infected well (pooling three replicate wells) and, if necessary, retained for the VYR portion of the study. Alternatively, separate plates can be prepared and frozen for the VYR assay. After maximum CPE is observed, viable plates are stained with neutral red dye. Incorporated dye content is quantified as described above. Data generated from this portion of the study are neutral red _EC50 , _CC50 , and SI values. Compounds observed to be active above are further evaluated by the VYR assay. The VYR test is a direct determination of how well a test compound inhibits viral replication. Virus replicated in the presence of test compound is titrated and compared to virus from untreated infected controls. Titration of pooled virus samples (harvested as described above) is performed by end-point dilution. This is accomplished by titrating log ₁₀ dilutions of virus using three or four microwells per dilution on fresh monolayers of cells by end-point dilution. Wells are scored for the presence or absence of virus after a clear CPE (measured by neutral red uptake) is observed. Plotting the log ₁₀ of inhibitor concentration versus the log ₁₀ of virus produced at each concentration allows calculation of the 90% (1 log ₁₀ ) effective concentration by linear regression. The SI value for this test is obtained by dividing the EC ₉₀ by the CC ₅₀ obtained in part 1 of the assay.

[Example 153]
(2) Screening Assay for Lassa Virus (LASV) Primary Lassa Virus Assay. Confluent or near-confluent cell culture monolayers are prepared in 12-well disposable cell culture plates. Cells are maintained in DMEM supplemented with 10% FBS. For antiviral assays, the same medium is used, but the FBS is reduced to 2% or less and supplemented with 1% penicillin/streptomycin. Test compounds are prepared at four log ₁₀ final concentrations, usually 0.1, 1.0, 10 and 100 μg/ml or μM. Virus and cell controls are run in parallel with each test compound. In addition, a known active drug is tested as a positive control drug, using the same experimental setup as described for the virus and cell controls. A positive control is tested with each test run. The assay is initiated by first removing the growth medium from the 12-well plate of cells and infecting the cells with 0.01 MOI of LASV strain Josiah. Cells are incubated for 90 minutes: 500 μl inoculum/M12 well, at 37° C., 5% CO2, with constant gentle agitation. The inoculum is removed and cells are washed 2× with medium. Test compounds are then applied in a total volume of 1 ml of medium. Tissue culture supernatants (TCS) are harvested at the appropriate time points. TCS is then used to determine compound inhibitory effects on viral replication. Virus replicated in the presence of test compounds is titrated and compared to virus from untreated infected controls. For titration of TCS, serial 10-fold dilutions are prepared and used to infect fresh monolayers of cells. Cells are overlaid with 1% agarose mixed 1:1 with 2× MEM supplemented with 10% FBS and 1% penicillin, and the number of plaques is determined. Plotting the log ₁₀ of inhibitor concentration versus the log ₁₀ of virus produced at each concentration allows calculation of the 90% (1 log ₁₀ ) effective concentration by linear regression.

Secondary Lassa Virus Assay. The secondary assay involves a similar methodology to that described in the previous paragraph using 12-well plates of cells. Differences are noted in this section. Cells are infected as described above, but this time overlaid with 1% agarose diluted 1:1 in 2X MEM, supplemented with 2% FBS and 1% penicillin/streptomycin, and supplemented with the corresponding drug concentration. Cells are incubated at 37° C. with 5% CO2 for 6 days. The overlay is then removed and plates are stained with 0.05% crystal violet in 10% buffered formalin for approximately 20 minutes at room temperature. Plates are then washed and dried, and the number of plaques is counted. The number of plaques at each set of compound dilutions is converted to a percentage relative to the untreated virus control. The 50% effective (EC50, virus inhibitory) concentration is then calculated by linear regression analysis.

[Example 154]
(3) Screening Assays for Ebola Virus (EBOV) and Nipah Virus (NIV) Primary Ebola/Nipah Virus Assay. A four-concentration plaque reduction assay is performed. Confluent or near-confluent cell culture monolayers are prepared in 12-well disposable cell culture plates. Cells are maintained in DMEM supplemented with 10% FBS. For antiviral assays, the same medium is used, but the FBS is reduced to 2% or less and supplemented with 1% penicillin/streptomycin. Test compounds are prepared at four log ₁₀ final concentrations, typically 0.1, 1.0, 10 and 100 μg/ml or μM. Virus and cell controls are run in parallel with each test compound. In addition, a known active drug is tested as a positive control drug using the same experimental setup as described for the virus and cell controls. A positive control is tested with each test run. The assay is initiated by first removing the growth medium from the 12-well plate of cells. Test compounds are then applied to the wells at a 2X concentration in a volume of 0.1 ml. Virus is placed in those wells designated for virus infection, usually in a volume of 0.1 ml at approximately 200 plaque forming units. Virus-free medium is placed in toxicity control wells and cell control wells. Virus control wells are treated similarly with virus. The plates are incubated at 37°C with 5% _CO2 for 1 hour. The virus-compound inoculum is removed, the cells are washed and overlaid with 1.6% tragacanth diluted 1:1 in 2X MEM, supplemented with 2% FBS and 1% penicillin/streptomycin, and supplemented with the corresponding drug concentration. The cells are incubated at 37°C with 5% _CO2 for 10 days. The overlay is then removed and the plates are stained with 0.05% crystal violet in 10% buffered formalin for approximately 20 minutes at room temperature. The plates are then washed, dried, and the number of plaques counted. The number of plaques in each set of compound dilutions is converted to a percentage of the untreated virus control. The 50% effective (EC ₅₀ , virus inhibitory) concentration is then calculated by linear regression analysis.

Secondary Ebola/Nipah virus assay using VYR components. The secondary assay involves a similar methodology to that described in the previous paragraph using 12-well plates of cells. Differences are noted in this section. Eight half-log ₁₀ concentrations of inhibitors are tested for antiviral activity. One positive control drug is tested for each batch of compound evaluated. For this assay, cells are infected with virus. Cells are infected as described above, but this time incubated in DMEM supplemented with 2% FBS and 1% penicillin/streptomycin and the corresponding drug concentration. Cells are incubated at 37° C. with 5% CO ₂ for 10 days and observed daily under a microscope for the number of green fluorescent cells. An aliquot of supernatant from the infected cells is taken daily and three replicate wells are pooled. The pooled supernatant is then used to determine compound inhibitory effects on viral replication. Virus replicated in the presence of the test compound is titrated and compared to virus from an untreated infected control. For titration of pooled virus samples, serial 10-fold dilutions are prepared and used to infect fresh monolayers of cells. Cells are overlaid with tragacanth and the number of plaques determined. Plotting the log ₁₀ of inhibitor concentration versus the log ₁₀ of virus produced at each concentration allows calculation of the 90% (1 log ₁₀ ) effective concentration by linear regression.

[Example 155]
Anti-Dengue virus cytoprotection assay:
Cell preparation - BHK21 cells (Syrian golden hamster kidney cells, ATCC catalog number CCL-I0), Vero cells (African green monkey kidney cells, ATCC catalog number CCL-81), or Huh-7 cells (human hepatocellular carcinoma) were passaged in T-75 flasks in DMEM supplemented with 10% FBS, 2 mM L-glutamine, 100 U/mL penicillin, and 100 μg/mL streptomycin prior to use in the antiviral assay. The day before the assay, cells were split 1:2 to ensure that they were in exponential growth phase at the time of infection. Total cell and viability quantification was performed using a hemacytometer and trypan blue dye exclusion. Cell viability was greater than 95% for cells to be utilized in the assay. Cells were resuspended in tissue culture medium at ^3x103 ( ^5x105 for Vero and Huh-7 cells) cells per well and added to flat-bottom microtiter plates in a volume of 100 μL. Plates were incubated overnight at 37°C/5% _CO2 to allow cell attachment. Monolayers were observed to be approximately 70% confluent.

Virus preparation - Dengue virus type 2 New Guinea C strain was obtained from ATCC (catalog number VR-1584) and grown in LLC-MK2 (rhesus monkey kidney cells; catalog number CCL-7.1) cells for generation of stock virus pools. Aliquots of virus pre-titrated in BHK21 cells were removed from the freezer (-80°C) and allowed to thaw slowly to room temperature in a biological safety cabinet. Virus was resuspended and diluted in assay medium (DMEM supplemented with 2% heat-inactivated FBS, 2 mM L-glutamine, 100 U/mL penicillin, and 100 μg/mL streptomycin) such that the amount of virus added to each well in a volume of 100 μL was the amount determined to obtain 85% to 95% cell killing at 6 days post-infection.

Plate format - Each plate contains cell control wells (cells only), virus control wells (cells plus virus), triplicate drug toxicity wells per compound (cells plus drug only), and triplicate experimental wells (drug plus cells plus virus).

Potency and Toxicity XTT - Following incubation at 37°C in a 5% _CO2 incubator, test plates were stained with the tetrazolium dye XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide). XTT-tetrazolium is metabolized to a soluble formazan product by mitochondrial enzymes of metabolically active cells, allowing rapid quantitative analysis of inhibition of virus-induced cell killing by antiviral test substances. XTT solution was prepared daily as a 1 mg/mL stock in RPMI 1640. Phenazine methosulfate (PMS) solution was prepared at 0.15 mg/mL in PBS and stored at -20°C in the dark. XTT/PMS stocks were prepared immediately prior to use by adding 40 μL of PMS per ml of XTT solution. Fifty microliters of XTT/PMS was added to each well of the plate and the plate was reincubated for 4 hours at 37° C. The plate was sealed with an adhesive plate seal, gently shaken or inverted several times to mix the soluble formazan product, and the plate was read spectrophotometrically at 450/650 nm using a Molecular Devices Vmax plate reader.

Data Analysis - Raw data was collected from Softmax Pro 4.6 software and imported into a Microsoft Excel spreadsheet for analysis. The percent reduction in viral cytopathic effect compared to untreated virus control was calculated for each compound. Percent cell control values were calculated for each compound and compared to drug-treated uninfected cells in media alone to uninfected cells.

[Example 156]
Anti-RSV cytoprotection assay:
Cell preparation - HEp2 cells (human epithelial cells, ATCC catalogue no. CCL-23) were passaged in DMEM supplemented with 10% FBS, 2 mM L-glutamine, 100 U/mL penicillin, 100 μg/mL streptomycin, 1 mM sodium pyruvate and 0.1 mM NEAA in T-75 flasks prior to use in the antiviral assay. The day before the assay, cells were split 1:2 to ensure they were in exponential growth phase at the time of infection. Total cell and viability quantification was performed using a hemacytometer and trypan blue dye exclusion. Cell viability was greater than 95% for cells to be utilized in the assay. Cells were resuspended in tissue culture medium at 1× ¹⁰⁴ cells per well and added to flat-bottom microtiter plates in a volume of 100 μL. Plates were incubated overnight at 37° C./5% _CO2 to allow cell attachment. Virus Preparation - RSV strain Long and RSV strain 9320 were obtained from ATCC (catalog numbers VR-26 and VR-955, respectively) and grown in HEp2 cells for generation of stock virus pools. Pre-titrated aliquots of virus were removed from the freezer (-80°C) and allowed to thaw slowly to room temperature in a biological safety cabinet. Virus was resuspended and diluted in assay medium (DMEM supplemented with 2% heat-inactivated FBS, 2 mM L-glutamine, 100 U/mL penicillin, 100 μg/mL streptomycin, 1 mM sodium pyruvate and 0.1 mM NEAA) such that the amount of virus added to each well in a volume of 100 μL was the amount determined to obtain 85% to 95% cell killing at 6 days post-infection. Potency and toxicity XTT plates were stained and analyzed as previously described for the dengue cell protection assay.

[Example 157]
Anti-influenza virus cell protection assay:
Cell preparation - MOCK cells (canine kidney cells, ATCC catalogue no. CCL-34) were passaged in DMEM supplemented with 10% FBS, 2 mM L-glutamine, 100 U/mL penicillin, 100 μg/mL streptomycin, 1 mM sodium pyruvate and 0.1 mM NEAA in T-75 flasks prior to use in the antiviral assay. The day before the assay, cells were split 1:2 to ensure they were in exponential growth phase at the time of infection. Total cell and viability quantification was performed using a hemacytometer and trypan blue dye exclusion. Cell viability was greater than 95% for cells to be utilized in the assay. Cells were resuspended in tissue culture medium at 1× ¹⁰⁴ cells per well and added to flat-bottom microtiter plates in a volume of 100 μL. Plates were incubated overnight at 37° C./5% _CO2 to allow cell attachment.

Virus preparation - Influenza A/PR/8/34 (ATCC number VR-95), A/CA/05/09 (CDC), A/NY/18/09 (CDC), and A/NWS/33 (ATCC number VR-219) strains were obtained from the ATCC or the Center for Disease Control and grown in MDCK cells for generation of stock virus pools. Pre-titrated aliquots of virus were removed from the freezer (-80°C) and allowed to thaw slowly to room temperature in a biological safety cabinet. Virus was resuspended and diluted in assay medium (DMEM supplemented with 0.5% BSA, 2 mM L-glutamine, 100 U/mL penicillin, 100 μg/mL streptomycin, 1 mM sodium pyruvate, 0.1 mM NEAA, and 1 μg/ml TPCK-treated trypsin) such that the amount of virus added to each well in a volume of 100 μL was the amount determined to obtain 85% to 95% cell killing at 4 days post-infection. Potency and toxicity XTT plates were stained and analyzed as previously described for the dengue cell protection assay.

[Example 158]
Anti-Hepatitis C Virus Assay:
Cell Culture - The reporter cell line Huh-luc/neo-ET was obtained from Dr. Ralf Bartenschlager (Department of Molecular Virology, Hygiene Institute, University of Heidelberg, Germany) through a specific license agreement by ImQuest Biosciences. This cell line harbors a persistently replicating l ₃₈₉ luc-ubi-neo/NS3-3'ET replicon containing a firefly luciferase gene-ubiquitin-neomycin phosphotransferase fusion protein containing ET tissue culture adaptation mutations (E1202G, T12081 and K1846T) and the EMCV IRES-driven NS3-5B HCV coding sequence. Stock cultures of Huh-luc/neo-ET were expanded by culturing in DMEM supplemented with 10% FCS, 2 mM glutamine, penicillin (100 μU/mL)/streptomycin (100 μg/mL) and 1× non-essential amino acids plus 1 mg/mL G418. Cells were split 1:4 and cultured in the same medium plus 250 μg/mL G418 for two passages. Cells were treated with trypsin, counted by staining with trypan blue, seeded into 96-well tissue culture plates at a cell culture density of 7.5×10 ³ cells per well, and incubated at 37° C., 5% CO ₂ for 24 hours. Following 24 hours of incubation, the medium was removed and replaced in triplicate with the same medium minus G418 plus test compound. Six wells in each plate received medium alone as untreated controls. Cells were incubated for an additional 72 hours at 37° C., 5% CO ₂ , and then anti-HCV activity was measured by luciferase endpoint. Duplicate plates were treated and incubated in parallel for determination of cytotoxicity by XTT staining.

Cell viability - Cell culture monolayers from treated cells were stained with the tetrazolium dye XTT to assess cell viability of the Huh-luc/neo-ET reporter cell line in the presence of the compound.

Measurement of viral replication - HCV replication from the replicon assay system was measured by luciferase activity using the britelite plus luminescent reporter gene kit according to the manufacturer's instructions (Perkin Elmer, Shelton, CT). Briefly, one vial of britelite plus lyophilized substrate was solubilized in 10 mL of britelite reconstitution buffer and mixed gently by inversion. After 5 minutes of incubation at room temperature, britelite plus reagent was added to a 96-well plate at 100 μL per well. The plate was sealed with adhesive film and incubated at room temperature for approximately 10 minutes to lyse the cells. Well contents were transferred to a white 96-well plate and luminescence was measured within 15 minutes using a Wallac 1450 Micro beta Trilux liquid scintillation counter. Data was imported into a customized Microsoft Excel 2007 spreadsheet for determination of 50% viral inhibitory concentrations (EC ₅₀ ).

[Example 159]
Anti-parainfluenza-3 cytoprotection assay:
Cell preparation - HEp2 cells (human epithelial cells, ATCC catalogue no. CCL-23) were passaged in DMEM supplemented with 10% FBS, 2 mM L-glutamine, 100 U/mL penicillin, 100 μg/mL streptomycin, 1 mM sodium pyruvate and 0.1 mM NEAA in T-75 flasks prior to use in the antiviral assay. The day before the assay, cells were split 1:2 to ensure they were in exponential growth phase at the time of infection. Total cell and viability quantification was performed using a hemacytometer and trypan blue dye exclusion. Cell viability was greater than 95% for cells to be utilized in the assay. Cells were resuspended in tissue culture medium at 1× ¹⁰⁴ cells per well and added to flat-bottom microtiter plates in a volume of 100 μL. Plates were incubated overnight at 37° C./5% _CO2 to allow cell attachment.

Virus preparation - Parainfluenza virus type 3 SF4 strain was obtained from ATCC (catalog number VR-281) and grown in HEp2 cells for generation of stock virus pools. Pre-titrated aliquots of virus were removed from the freezer (-80°C) and allowed to thaw slowly to room temperature in a biological safety cabinet. Virus was resuspended and diluted in assay medium (DMEM supplemented with 2% heat-inactivated FBS, 2 mM L-glutamine, 100 U/mL penicillin, and 100 μg/mL streptomycin) such that the amount of virus added to each well in a volume of 100 μL was the amount determined to obtain 85% to 95% cell killing at 6 days post-infection.

Plate format - each plate contains cell control wells (cells only), virus control wells (cells plus virus), triplicate drug toxicity wells per compound (cells plus drug only), and triplicate experimental wells (drug plus cells plus virus). Potency and Toxicity XTT - following incubation at 37°C in a 5% _CO2 incubator, test plates were stained with the tetrazolium dye XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazole hydroxide). XTT-tetrazolium is metabolized by mitochondrial enzymes of metabolically active cells to a soluble formazan product allowing rapid quantitative analysis of inhibition of virus-induced cell killing by antiviral test substances. XTT solution was prepared daily as a 1 mg/mL stock in RPMI 1640. Phenazine methosulfate (PMS) solution was prepared at 0.15 mg/mL in PBS and stored in the dark at -20°C. XTT/PMS stock was prepared immediately prior to use by adding 40 μL of PMS per ml of XTT solution. Fifty microliters of XTT/PMS was added to each well of the plate and the plate was reincubated at 37°C for 4 hours. The plate was sealed with an adhesive plate sealer, the soluble formazan product was mixed by gentle shaking or inversion several times and the plate was read spectrophotometrically at 450/650 nm using a Molecular Devices Vmax plate reader.

Data Analysis - Raw data was collected from Softmax Pro 4.6 software and imported into a Microsoft Excel spreadsheet for analysis. The percent reduction in viral cytopathic effect compared to untreated virus control was calculated for each compound. Percent cell control values were calculated for each compound and compared to drug-treated uninfected cells in media alone to uninfected cells.

[Example 160]
Influenza polymerase inhibition assay:
Virus preparation - Purified influenza virus A/PR/8/34 (1 ml) was obtained from Advanced Biotechnologies, Inc. (Columbia, MD), thawed, aliquoted into 5 aliquots, and stored at -80°C until use. On the day of assay initiation, 20 μL of 2.5% Triton N-101 was added to 180 μL of purified virus. The disrupted virus was diluted 1:2 in a solution containing 0.25% Triton and PBS. The disruption provided a source of influenza ribonucleoproteins (RNPs) containing influenza RNA-dependent RNA polymerase and template RNA. Samples were stored on ice until use in the assay.

Polymerase Reactions - Each 50 μL polymerase reaction contained: 5 μL disrupted RNP, 100 mM Tris-HCl (pH 8.0), 100 mM KCl, 5 mM MgCl ₂ , 1 mM dithiothreitol, 0.25% Triton N-101, 5 μCi of [α- ³² P]GTP, 100 μM ATP, 50 μM each (CTP, UTP), 1 μM GTP, and 200 μM adenyl (3'-5') guanosine. To test inhibitors, reactions contained the inhibitor and the same was done for reactions containing a positive control (2'-deoxy-2'-fluoroguanosine-5'-triphosphate). Other controls included RNP + reaction mix, and RNP + 1% DMSO. The reaction mixture without ApG primers and NTPs was incubated at 30°C for 20 min. Once ApG and NTPs were added to the reaction mixture, the samples were incubated at 30°C for 1 h, followed immediately by transfer of the reactions to glass fiber filter plates and subsequent precipitation with 10% trichloroacetic acid (TCA). The plates were then washed five times with 5% TCA, followed by one wash with 95% ethanol. Once the filters were dry, incorporation of [α- ^32P ]GTP was measured using a liquid scintillation counter (Micro beta).

Plate format - Each test plate contained triplicate samples of three compounds (6 concentrations) in addition to triplicate samples of RNP + reaction mix (RNP alone), RNP + 1% DMSO, and reaction mix alone (no RNP).

Data Analysis - Raw data was collected from a Micro Beta scintillation counter. Incorporation of radioactive GTP directly correlates with the level of polymerase activity. "Percent inhibition values" were obtained by dividing the mean value of each test compound by the RNP + 1% DMSO control. The mean obtained at each concentration of 2DFGTP was compared to the RNP + reaction control. Data was then imported into a Microsoft Excel spreadsheet and _IC50 values were calculated by linear regression analysis.

[Example 161]
HCV polymerase inhibition assay:
The activity of compounds for the inhibition of HCV polymerase was evaluated using a previously described method (Lam et al. 2010. Antimicrobial Agents and Chemotherapy 54(8):3187-3196). HCV NS5B polymerase assays were performed in a volume of 20 μL in 96-well reaction plates. Each reaction contained 40 ng/μL of purified recombinant NS5BΔ22 genotype-1b polymerase, 20 ng/μL of HCV genotype-1b complementary IRES template, 1 μM each of the four natural ribonucleotides, 1 U/mL Optizyme RNAse inhibitor (Promega, Madison, WI), ₁ mM MgCl , 0.75 mM MnCl , and ₂ mM dithiothreitol (DTT) in 50 mM HEPES buffer (pH 7.5). The reaction mixture was assembled on ice in two steps. Step 1 consisted of combining all reaction components except the natural nucleotides and labeled UTP in the polymerase reaction mixture. Ten microliters (10 μL) of the polymerase mixture were dispensed into individual wells of a 96-well reaction plate on ice. Polymerase reaction mix without NS5B polymerase was included as a no enzyme control. Serial half-log dilutions of the test and control compounds, 2'-0-methyl-CTP and 2'-0-methyl-GTP (Trilink, San Diego, CA), were prepared in water and 5 μL of serially diluted compound or water alone (no compound control) was added to wells containing the polymerase mix. Five microliters of the nucleotide mix (natural nucleotides and labeled UTP) was then added to the reaction plate wells and the plate was incubated at 27°C for 30 minutes. The reaction was quenched with the addition of 80 μL of stop solution (12.5 mM EDTA, 2.25 M NaCl, and 225 mM sodium citrate) and the RNA products were applied under vacuum pressure to a Hybond-N+ membrane (GE Healthcare, Piscataway, N.J.) using a dot blot apparatus. The membrane was removed from the dot blot apparatus and washed four times with 4× SSC (0.6 M NaCl, and 60 mM sodium citrate), then rinsed once with water and once with 100% ethanol. The membrane was air-dried, exposed to a phosphorimaging screen, and images were captured using a Typhoon 8600 Phosphoimager. Following image capture, membranes were placed into a Micro beta cassette with scintillation fluid and the CPM in each reaction were counted on a Micro beta 1450. CPM data was imported into a custom Excel spreadsheet for compound _IC50 determination.

[Example 162]
NS5B RNA-dependent RNA polymerase reaction conditions Compounds were assayed for inhibition of NS5B-δ21 from HCV GT-1b Con-1. Reactions contained purified recombinant enzyme, 1 u/μL negative-stranded HCV IRES RNA template, and 1 μM NTP substrates including either [ ³² P]-CTP or [ ³² P]-UTP. Assay plates were incubated at 27° C. for 1 hour before quenching. [ ³² P] incorporation into macromolecular products was determined by filter binding.

[Example 163]
Human DNA polymerase inhibition assay:
Human DNA polymerase alpha (catalog no. 1075), beta (catalog no. 1077), and gamma (catalog no. 1076) were purchased from CHIMERx (Madison, WI). Inhibition of beta and gamma DNA polymerase activity was assayed in 50 uL reaction mixtures in microtiter plates containing 50 mM Tris-HCl (pH 8.7), KCl (10 mM for beta and 100 mM for gamma), 10 mM MgCl ₂ , 0.4 mg/mL BSA, 1 mM DTT, 15% glycerol, 0.05 mM dCTP, dTTP, and dATP, 10 uCi of [ ³² P]-alpha-dGTP (800 Ci/mmol), 20 ug activated calf thymus DNA, and test compound at the indicated concentrations. The alpha DNA polymerase reaction mixture was as follows in a volume of 50 uL per sample: 20 mM Tris-HCl (pH 8), 5 mM magnesium acetate, 0.3 mg/mL BSA, 1 mM DTT, 0.1 mM spermine, 0.05 mM dCTP, dTTP and dATP, 10 uCi of [ ³² P]-alpha-dGTP (800 Ci/mmol), 20 ug of activated calf thymus DNA, and test compound at the indicated concentrations. For each assay, the enzyme reaction was allowed to proceed for 30 minutes at 37° C., followed by transfer onto glass-fiber filter plates and subsequent precipitation with 10% trichloroacetic acid (TCA). The plates were then washed with 5% TCA, followed by one wash with 95% ethanol. Once the filters were dry, the incorporation of radioactivity was measured using a liquid scintillation counter (Micro beta).

[Example 164]
HIV-infected PBMC assay:
Fresh human peripheral blood mononuclear cells (PBMCs) were obtained from a commercial source (Biological Specialty) and determined to be seronegative for HIV and HBV. Leukodepleted blood cells were washed several times with PBS depending on the volume of donor blood obtained. After washing, leukodepleted blood was diluted 1:1 with Dulbecco's phosphate buffered saline (PBS) and layered with 15 mL of Ficoll-Hypaque density gradient in 50 ml conical centrifuge tubes. The tubes were centrifuged at 600 g for 30 minutes. Banded PBMCs were gently aspirated from the resulting interface and washed three times with PBS. After a final wash, cell numbers were determined by trypan blue dye exclusion and cells were resuspended at 1x106 ^cells /mL in RPMI 1640 with 15% fetal bovine serum (FBS), 2mmol/L L-glutamine, 2ug/mL PHA-P, 100U/mL penicillin and 100ug/mL streptomycin and incubated at 37°C for 48-72 hours. After incubation, PBMCs were centrifuged and resuspended in tissue culture medium. Cultures were maintained by half-volume culture changes with fresh IL-2-containing tissue culture medium every 3 days until use. Assays were initiated with PBMCs 72 hours after PHA-P stimulation.

To minimize the effect of donor variability, the PBMCs used in the assay were a mixture of cells derived from three donors. Immediately prior to use, target cells were resuspended in fresh tissue culture medium at ^1x106 cells/mL and plated at 50uL/well in the inner wells of a 96-well round-bottom microtiter plate. 100uL of a 2X concentration of compound-containing medium was then transferred to the 96-well plate containing cells in 50uL of medium. AZT was used as an internal assay standard.

Following addition of test compounds to the wells, 50 uL of HIV virus at a given dilution (prepared from 4X the final desired in-well concentration) was added and mixed well. For infection, 50-150 TCID ₅₀ of each virus was added per well (final MOI approximately 0.002). PBMCs were exposed to viruses in triplicate and cultured in 96-well microtiter plates in the presence or absence of test materials at varying concentrations as described above. After 7 days in culture, HIV-1 replication was quantified in tissue culture supernatants by measurement of reverse transcriptase (RT) activity. Only wells with cells and virus served as virus controls. Another plate was prepared identically without virus for drug cytotoxicity studies.

Reverse transcriptase activity assay - Reverse transcriptase activity was measured in cell-free supernatants using a standard radioactive incorporation polymerization assay. Tritiated thymidine triphosphate (TTP; New England Nuclear) was purchased at 1 Ci/mL and 1 uL was used per enzymatic reaction. rAdT stock solution was prepared by mixing 0.5 mg/mL poly rA and 1.7 U/mL oligo dT in distilled water and stored at -20°C. RT reaction buffer was prepared fresh daily and consisted of 125 uL 1 mol/L EGTA, ₁₂₅ uL dH2O, 125 uL 20% TritonX-100, 50 uL 1 mol/L Tris (pH 7.4), 50 uL 1 mol/L DTT, and 40 uL 1 mol/L _MgCl2 . For each reaction, 1 uL TTP, ₄ uL dH2O, 2.5 uL rAdT, and 2.5 uL reaction buffer were mixed. Ten microliters of this reaction mixture was placed into a round-bottom microtiter plate, and 15 uL of virus-containing supernatant was added and mixed. The plate was incubated at 37°C in a humidified incubator for 90 minutes. Following incubation, 10 uL of the reaction volume was spotted onto a DEAE filtermat in the appropriate plate format, washed five times (5 min each) in 5% sodium phosphate buffer, two times (1 min each) in distilled water, and two times (1 min each) in 70% ethanol, then air-dried. The dried filtermat was placed into a plastic sleeve, and 4 mL of Opti-FluorO was added to the sleeve. Incorporated radioactivity was quantified using a Wallac 1450 Micro beta Trilux liquid scintillation counter.

[Example 165]
HBV:
HepG2.2.15 cells (100 μL) in RPMI 1640 medium with 10% fetal bovine serum were added to all wells of a 96-well plate at a density of 1× ¹⁰⁴ cells per well, and the plate was incubated for 24 hours at 37° C. in a 5% _CO2 environment. Following incubation, six 10-fold serial dilutions of test compounds prepared in RPMI 1640 medium with 10% fetal bovine serum were added in triplicate to individual wells of the plate. Six wells in the plate received medium alone as a virus-only control. The plate was incubated for six days at 37° C. in a 5% _CO2 environment. The culture medium was changed on day 3 to medium containing the indicated concentrations of each compound. One hundred microliters of supernatant was collected from each well for analysis of viral DNA by qPCR, and cytotoxicity was assessed by XTT staining of cell culture monolayers on day 6.

Ten microliters of cell culture supernatant harvested on day 6 was diluted in qPCR dilution buffer (40 μg/mL sheared salmon sperm DNA) and boiled for 15 min. Quantitative real-time PCR was performed in 386-well plates using an Applied Biosystems 7900HT Sequence Detection System and supporting SDS2.4 software. Platinum Quantitative PCR SuperMix-UDG (Invitrogen) and specific DNA oligonucleotide primers (IDT, Coralville, ID) HBV-AD38-qFl (5′-CCG TCT GTG CCT TCT CAT CTG-3′), HBV-AD38-qRl (5′-AGT CCA AGA GTY CTC TTA TRY AAG ACC TT3′), and HBV-AD38-qPl (5′-FAM CCG TGT GCA /ZEN/CTT CGC TTC ACC TCT Five microliters (5 μL) of boiled DNA for each sample and serial 10-fold dilutions of quantitative DNA standards were subjected to real-time Q-PCR using SDS.24 software (SDS-3'BHQ1) at a final concentration of 0.2 μM for each primer in a total reaction volume of 15 μL. The HBV DNA copy number in each sample was interpolated from the standard curve by SDS.24 software, and the data was imported into an Excel spreadsheet for analysis.

The 50% cytotoxicity concentration for test materials is derived by measuring the reduction of the tetrazolium dye XTT in treated tissue culture plates. XTT is metabolized to a soluble formazan product in metabolically active cells by the mitochondrial enzyme NADPH oxidase. XTT solution was prepared daily as a 1 mg/mL stock in PBS. Phenazine methosulfate (PMS) stock solution was prepared at 0.15 mg/mL in PBS and stored at -20°C in the dark. XTT/PMS solutions were prepared immediately prior to use by adding 40 μL of PMS per mL of XTT solution. Fifty microliters of XTT/PMS were added to each well of the plate and the plate was incubated at 37°C for 2-4 hours. The 2-4 hour incubation has been empirically determined to be within the linear response range for XTT dye reduction using the indicated number of cells for each assay. An adhesive plate sealer was used in place of a lid, the sealed plate was inverted several times to mix the soluble formazan product, and the plate was read at 450 nm (reference wavelength of 650 nm) using a Molecular Devices SpectraMax Plus 384 spectrophotometer. Data was collected by Softmax 4.6 software and imported into an Excel spreadsheet for analysis.

[Example 166]
Dengue RNA-dependent RNA polymerase reaction conditions RNA polymerase assays were performed at 30°C using 100 μl of reaction mix in 1.5 ml tubes. Final reaction conditions were 50 mM Hepes (pH 7.0), 2 mM DTT, 1 mM MnCl ₂ , 10 mM KCl, 100 nM UTR-Poly A (self-annealing primer), 10 μM UTP, 26 nM RdRp enzyme. Reaction mixes with different compounds (inhibitors) were incubated for 1 hour at 30°C. To determine the amount of pyrophosphate generated during the polymerase reaction, 30 μl of the polymerase reaction mix was mixed with luciferase-coupled enzyme reaction mix (70 μl). The final reaction conditions for the luciferase reaction were ₅ mM MgCl2, 50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 200 μU ATP sulfurylase, 5 μM APS, 10 nM luciferase, 100 μM D-luciferin. The white plate containing the reaction samples (100 μl) was immediately transferred to a luminometer Veritas (Turner Biosystems, CA) for detection of the light signal.

Claims (6)

1. A composition for use in the treatment of infections caused by RNA and DNA viruses , comprising a compound of the formula:

[Wherein,
^R1 is H, monophosphate, diphosphate, or triphosphate;
Z is CH;
^R7 is H;
^R3 is H;
^R4 is hydroxyl;
^R5 is hydroxyl;
^R6 is H.
or a pharma- ceutical acceptable salt thereof,
The composition, wherein the RNA and DNA viruses are selected from West Nile Virus (WNV), Enterovirus 68, and Dengue Virus . The composition of claim 1 , wherein R ¹ is a triphosphate. The composition of claim 1 , wherein R ¹ is H. The composition according to any one of claims 1 to 3 , wherein said composition is for use in the treatment of an infection caused by Enterovirus 68 . The composition according to any one of claims 1 to 3, wherein the composition is for use in the treatment of an infection caused by West Nile Virus (WNV). 4. The composition of any one of claims 1 to 3, wherein the composition is for use in treating an infection caused by dengue virus genotype 1, dengue virus genotype 2, dengue virus genotype 3, dengue virus genotype 4 , or a combination thereof.

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